Bio


Dr. Frankovich is a Clinical Professor in the Department of Pediatrics, Division of Allergy, Immunology Rheumatology (AIR) at Stanford University/Lucile Packard Children’s Hospital (LPCH). Her clinical expertise is in systemic inflammatory and autoimmune diseases that co-occur with psychiatric symptoms. She completed her training in pediatrics, pediatric rheumatology, and clinical epidemiology at Stanford University/LPCH. She directs the Stanford PANS Program (2012- present) where she and her collaborators have created a longitudinal clinical database and large biorepository of patient and healthy control biospecimens. In addition to generating clinical data to better understand immune-behavioral health conditions, she is collaborating with 10 basic science labs who aim to understand the immunological underpinnings of PANS and related conditions.

Clinical Focus


  • Pediatric Acute Onset Neuropsychiatric Syndrome (PANS)
  • Pediatric Rheumatology

Administrative Appointments


  • PANS Program Director, Stanford Children's Hospital (2012 - Present)
  • Clinical Assistant Professor, now Professor, Pediatric Rheumatology, Stanford Children’s Hospital (2010 - Present)
  • Instructor, General Pediatrics & Pediatric Rheumatology, Stanford Children's Hospital (2008 - 2010)

Honors & Awards


  • Clinical Science Research Award, Stanford Medicine, Department of Pediatrics (2020)
  • Junior Faculty, Clinical Award of Excellence, Stanford Children's Hospital (2014)

Boards, Advisory Committees, Professional Organizations


  • Scientific and Medical Advisory Board Member, The Alex Manfull Fund (2023 - Present)
  • Biospecimen Use Committee Member, POND Brain Bank (2022 - Present)
  • Advisory Committee Member, Stanford Medicine Biobank (2019 - Present)
  • Scientific and Medical Advisor, Brain Inflammation Collaborative (2022 - Present)
  • Scientific Advisory Board Member, Open Medicine Foundation (2019 - Present)
  • Scientific and Clinical Advisory Board Member, Neuroimmune Foundation (2021 - Present)

Professional Education


  • Residency: Stanford Health Care at Lucile Packard Children's Hospital (2004) CA
  • Fellowship: Stanford University Pediatric Rheumatology Fellowship (2008) CA
  • Masters, Stanford University, Clinical Epidemiology (2009)
  • Board Certification: American Board of Pediatrics, Pediatric Rheumatology (2009)
  • Board Certification: American Board of Pediatrics, Pediatrics (2004)

Current Research and Scholarly Interests


My primary interest and role at Stanford is to evaluate and treat children with both systemic and organ specific autoimmune disease. In October of 2012, we started a multidisciplinary clinic dedicated to treating patients with PANS (Pediatric Acute-onset Neuropsychiatric Syndromes). I am currently the clinical and research director for the PANS program.

Clinical Trials


  • Neurobiologic, Immunologic, and Rheumatologic Markers in Youth With PANS Recruiting

    This study is an investigation of the neurologic, immunologic, and rheumatologic markers of Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). PANS is a condition characterized by the abrupt, dramatic onset of obsessive compulsive disorder (OCD) and/or eating restriction accompanied by equally abrupt and severe co-morbid neuropsychiatric symptoms, which include anxiety, emotional lability, depression, irritability, aggression, oppositionality, deterioration in school performance, behavioral (developmental) regression, sensory amplification, movement abnormalities, sleep disturbance, and urinary frequency. PANS is thought to be caused by infection, inflammation, or alternate triggers that is associated with a brain response that leads to these symptoms. The purpose of this study is to examine specific neurologic, immunologic, rheumatologic, and genomic, components in children with the acute-onset of psychiatric symptoms. This research may begin to uncover a much larger story of autoimmune processes that are involved in psychiatric disorders of childhood. By better understanding the etiologic components of psychiatric phenomenon, future treatments may be better targeted to underlying causes.

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  • Observational Study of Pediatric Rheumatic Diseases: The CARRA Registry Recruiting

    Continuation of the CARRA Registry as described in the protocol will support data collection on patients with pediatric-onset rheumatic diseases. The CARRA Registry will form the basis for future CARRA studies. In particular, this observational registry will be used to answer pressing questions about therapeutics used to treat pediatric rheumatic diseases, including safety questions.

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2023-24 Courses


All Publications


  • Arthritis in Children with Psychiatric Deteriorations: A Case Series DEVELOPMENTAL NEUROSCIENCE Ma, M., Sandberg, J., Farhadian, B., Silverman, M., Xie, Y., Thienemann, M., Frankovich, J. 2023: 1

    Abstract

    Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS), Sydenham chorea and other post-infectious psychiatric deteriorations are thought to be caused by inflammatory/autoimmune mechanisms, likely involving the basal ganglia based on imaging studies. Patients have a relapsing-remitting course and some develop severe refractory psychiatric disease. We found that 55/193 (28%) of consecutive patients meeting PANS criteria developed chronic arthritis and 25/121 (21%) of those with related psychiatric deteriorations developed chronic arthritis. Here we describe 7 of these patients in detail and one sibling. Many of our patients often have "dry" arthritis (no effusions found on physical exam), but subtle effusions detected by imaging and features of spondyloarthritis, enthesitis, and synovitis. Joint capsule thickening, not previously reported in children, is a common finding in the presented cases and in psoriatic arthritis in adults. Due to the severity of psychiatric symptoms in some cases, which often overshadow joint symptoms, and concomitant sensory dysregulation (making the physical exam unreliable in the absence of effusions), we rely on imaging to improve sensitivity and specificity of the arthritis classification. We also report the immunomodulatory treatments of these 7 patients (initially non-steroidal anti-inflammatory drugs and disease-modifying anti-rheumatic drugs with escalation to biologic medications) and note any coincidental changes to their arthritis and psychiatric symptoms while on immunomodulation. Conclusion: Patients with overlapping psychiatric syndromes and arthritis may have a unifying cause and pose unique challenges; a multi-disciplinary team can utilize imaging to tailor and coordinate treatment for this patient population.

    View details for DOI 10.1159/000530854

    View details for Web of Science ID 001008111700001

    View details for PubMedID 37231875

  • Sex and Aggression Characteristics in a Cohort of Patients with Pediatric Acute-Onset Neuropsychiatric Syndrome. Journal of child and adolescent psychopharmacology Gao, J., Chan, A., Willett, T., Farhadian, B., Silverman, M., Tran, P., Ahmed, S., Thienemann, M., Frankovich, J. 2022

    Abstract

    Objective: This study describes for the first time the characteristics by sex of patients with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), including clinical phenotype, treatment, and psychosocial aspects of disease. Methods: This cross-sectional study included 205 consecutive community patients evaluated between January 1, 2012 and March 30, 2019 and compared 87 females with 118 males. Our primary hypothesis was that males would display more aggression, as measured by the Modified Overt Aggression Scale (MOAS) and would be treated with immunotherapy earlier than females. The MOAS began to be administered 5 years into the study period, and 57 of the 205 families completed the MOAS for this study. Results: Our analysis revealed that males had a higher median MOAS score in the first year of clinic when compared with females (median 11, interquartile range [IQR] [4-24] vs. median 3, IQR [1-9]; p = 0.03) and a higher median subscore for physical aggression (median 4, IQR [0-12] vs. median 0, IQR [0-8]; p = 0.05). The median time from PANS symptom onset to first administration of immunotherapy, which did not include nonsteroidal anti-inflammatory drugs or short bursts of oral steroids, was 6.9 years for females and 3.7 years for males (p = 0.20). The two groups did not differ significantly in age of PANS onset, time from onset to clinic entry, other psychiatric symptom measures, or laboratory markers of inflammation. Conclusion: Among patients with PANS, males exhibit more aggressive behavior when compared with females, which may advance the decision to treat with immunotherapy. Scores that capture a more global level of functioning show that despite there being a higher level of aggression in males, female patients with PANS have similar levels of overall impairment.

    View details for DOI 10.1089/cap.2021.0084

    View details for PubMedID 35998241

  • Children With PANS May Manifest POTS. Frontiers in neurology Chan, A., Gao, J., Houston, M., Willett, T., Farhadian, B., Silverman, M., Tran, P., Jaradeh, S., Thienemann, M., Frankovich, J. 2022; 13: 819636

    Abstract

    Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by an abrupt-onset of severe psychiatric symptoms including OCD, anxiety, cognitive difficulties, and sleep issues which is thought to be a post-infection brain inflammatory disorder. We observed postural orthostatic tachycardia syndrome (POTS) which resolved with immunomodulation in a patient with Pediatric acute-onset neuropsychiatric syndrome (PANS). Here, we aim to present a case of POTS and to examine the prevalence of (POTS) in our PANS cohort, and compare the clinical characteristics of patients with and without POTS.We conducted this cohort study of patients meeting PANS criteria who had at least three clinic visits during the study period. We included data from prospectively collected questionnaires and medical record review. We present a case followed by statistical comparisons within our cohort and a Kaplan-Meier analysis to determine the time-dependent risk of a POTS diagnosis.Our study included 204 patients: mean age of PANS onset was 8.6 years, male sex (60%), non-Hispanic White (78%). Evidence of POTS was observed in 19/204 patients (9%) with 5/19 having persistent POTS defined as persistent abnormal orthostatic vitals, persistent POTS symptoms, and/or continued need for pharmacotherapy for POTS symptoms for at least 6 months). In this PANS cohort, patients with POTS were more likely to have comorbid joint hypermobility (63 vs 37%, p = 0.04), chronic fatigue (42 vs 18%, p = 0.03), and a family history of chronic fatigue, POTS, palpitations and syncope. An unadjusted logistic regression model showed that a PANS flare (abrupt neuropsychiatric deterioration) was significantly associated with an exacerbation of POTS symptoms (OR 3.3, 95% CI 1.4-7.6, p < 0.01).Our study describes a high prevalence of POTS in patients with PANS (compared to the general population) and supports an association between POTS presentation and PANS flare within our cohort.

    View details for DOI 10.3389/fneur.2022.819636

    View details for PubMedID 35557616

    View details for PubMedCentralID PMC9086964

  • Profiling Behavioral and Psychological Symptoms in Children undergoing treatment for Spondyloarthritis and Polyarthritis. The Journal of rheumatology McHugh, A., Chan, A., Herrera, C., Park, J. M., Balboni, I., Gerstbacher, D., Hsu, J. J., Lee, T., Thienemann, M., Frankovich, J. 1800

    Abstract

    OBJECTIVE: Few studies examine psychopathology in different juvenile idiopathic arthritis (JIA) subtypes and disease activity states. We aimed to 1) Evaluate emotional and behavioral symptoms in children with spondyloarthritis (SpA) and polyarticular arthritis (PolyA) as compared to a national normative population using the Child Behavior Checklist (CBCL), and 2) Evaluate the relationship between CBCL scores and disease activity.METHODS: JIA patients aged 6-17 years with SpA or PolyA were recruited from our Pediatric Rheumatology clinic from April 2018 to April 2019 and the CBCL and Juvenile Arthritis Disease Activity Score (cJADAS10) were completed. Primary outcome measures were CBCL total competence, internalizing, externalizing and total problems raw scores. We compared outcomes from each group to national CBCL normative data. To investigate the relationship between CBCL scores and disease activity, we ran a generalized linear regression model for all arthritis patients with cJADAS10 as the main predictor.RESULTS: There were 111 patients and 1753 healthy controls. Compared to healthy controls, SpA or PolyA patients had worse total competence and internalizing scores. Higher cJADAS10 scores were associated with worse total competence, worse internalizing, and higher total problems scores. Most of these differences reached statistical significance (p<0.01). Self-harm/ suicidality was almost four-fold higher in patients with PolyA than healthy controls (OR 3.6, 95% CI 1.3-9.6, p=0.011).CONCLUSION: Our study shows that SpA and PolyA patients with more active disease have worse psychological functioning in activities, school and social arenas and more internalized emotional disturbances suggesting the need for regular mental health screening by rheumatologists.

    View details for DOI 10.3899/jrheum.210489

    View details for PubMedID 35105715

  • Patients with abrupt early-onset OCD due to PANS tolerate lower doses of antidepressants and antipsychotics. Journal of psychiatric research Thienemann, M., Park, M., Chan, A., Frankovich, J. 2021; 135: 270–78

    Abstract

    OBJECTIVE: To characterize drug tolerability in pediatric patients with an abrupt-onset of obsessive-compulsive disorder (OCD) meeting criteria for pediatric acute-onset neuropsychiatric syndrome (PANS).METHODS: We reviewed charts of 188 consecutive patients with PANS seen in the PANS clinic, collecting starting, side effect, and tolerated doses, as well as side effect profile for each antidepressant and antipsychotic trial.RESULTS: Of 188 included patients: 57% had trials of antidepressants and/or antipsychotics. Patients prescribed psychotropics were older at PANS onset (mean 9.5 vs 7.1 years, p<0.01) and had had a longer delay before presenting to clinic (median 1.4 vs 0.5 years, p<0.01). Antidepressant indications (n=146) were OCD (48%), anxiety (44%), and depression (32%). Antipsychotic indications (n=119) were aggression (34%), psychotic symptoms (28%), and OCD (24%). Side effects requiring medication change occurred in 54% of patients: in 38% of antidepressant trials and 49% of antipsychotic trials. Antidepressants' most common side effects were anxiety, agitation, aggression, and akathisia. Antipsychotics' most common side effects were dystonia, aggression, self-injurious behavior, and movement abnormality. Side effects were common at doses lower than the suggested starting doses for these medications. Patients tolerated antidepressants and antipsychotics when doses were low.CONCLUSION: When antidepressants and antipsychotics are prescribed to patients with PANS, intolerable side effects were noted at doses lower than or equal to suggested starting doses. Patients with PANS can benefit from these therapies. However, when treating these patients, clinicians are advised to start with significantly lower doses than they might use in other disorders.

    View details for DOI 10.1016/j.jpsychires.2021.01.022

    View details for PubMedID 33513473

  • Discovering prescription patterns in pediatric acute-onset neuropsychiatric syndrome patients. Journal of biomedical informatics Lopez Pineda, A., Pourshafeie, A., Ioannidis, A., McCloskey Leibold, C., Chan, A. L., Bustamante, C. D., Frankovich, J., Wojcik, G. L. 2020: 103664

    Abstract

    OBJECTIVE: Pediatric acute-onset neuropsychiatric syndrome (PANS) is a complex neuropsychiatric syndrome characterized by an abrupt onset of obsessive-compulsive symptoms and/or severe eating restrictions, along with at least two concomitant debilitating cognitive, behavioral, or neurological symptoms. A wide range of pharmacological interventions along with behavioral and environmental modifications, and psychotherapies have been adopted to treat symptoms and underlying etiologies. Our goal was to develop a data-driven approach to identify treatment patterns in this cohort.MATERIALS AND METHODS: In this cohort study, we extracted medical prescription histories from electronic health records. We developed a modified dynamic programming approach to perform global alignment of those medication histories. Our approach is unique since it considers time gaps in prescription patterns as part of the similarity strategy.RESULTS: This study included 43 consecutive new-onset pre-pubertal patients who had at least 3 clinic visits. Our algorithm identified six clusters with distinct medication usage history which may represent clinician's practice of treating PANS of different severities and etiologies i.e., two most severe groups requiring high dose intravenous steroids; two arthritic or inflammatory groups requiring prolonged nonsteroidal anti-inflammatory drug (NSAID); and two mild relapsing/remitting group treated with a short course of NSAID. The psychometric scores as outcomes in each cluster generally improved within the first two years.DISCUSSION: and conclusion Our algorithm shows potential to improve our knowledge of treatment patterns in the PANS cohort, while helping clinicians understand how patients respond to a combination of drugs.

    View details for DOI 10.1016/j.jbi.2020.103664

    View details for PubMedID 33359113

  • Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient. Neurology(R) neuroimmunology & neuroinflammation Cellucci, T., Van Mater, H., Graus, F., Muscal, E., Gallentine, W., Klein-Gitelman, M. S., Benseler, S. M., Frankovich, J., Gorman, M. P., Van Haren, K., Dalmau, J., Dale, R. C. 2020; 7 (2)

    Abstract

    OBJECTIVE: Autoimmune encephalitis (AE) is an important and treatable cause of acute encephalitis. Diagnosis of AE in a developing child is challenging because of overlap in clinical presentations with other diseases and complexity of normal behavior changes. Existing diagnostic criteria for adult AE require modification to be applied to children, who differ from adults in their clinical presentations, paraclinical findings, autoantibody profiles, treatment response, and long-term outcomes.METHODS: A subcommittee of the Autoimmune Encephalitis International Working Group collaborated through conference calls and email correspondence to consider the pediatric-specific approach to AE. The subcommittee reviewed the literature of relevant AE studies and sought additional input from other expert clinicians and researchers.RESULTS: Existing consensus criteria for adult AE were refined for use in children. Provisional pediatric AE classification criteria and an algorithm to facilitate early diagnosis are proposed. There is also discussion about how to distinguish pediatric AE from conditions within the differential diagnosis.CONCLUSIONS: Diagnosing AE is based on the combination of a clinical history consistent with pediatric AE and supportive diagnostic testing, which includes but is not dependent on antibody testing. The proposed criteria and algorithm require validation in prospective pediatric cohorts.

    View details for DOI 10.1212/NXI.0000000000000663

    View details for PubMedID 31953309

  • Familial Clustering of Immune-Mediated Diseases in Children with Abrupt-Onset Obsessive Compulsive Disorder. Journal of child and adolescent psychopharmacology Chan, A. n., Phu, T. n., Farhadian, B. n., Willett, T. n., Thienemann, M. n., Frankovich, J. n. 2020

    View details for DOI 10.1089/cap.2019.0167

    View details for PubMedID 32311283

  • Association of pediatric acute-onset neuropsychiatric syndrome with microstructural differences in brain regions detected via diffusion-weighted magnetic resonance imaging. JAMA Network Open Zheng, J., Frankovich, J., McKenna, E. S., Rowe, N. C., MacEachern, S. J., Ng, N. N., Tam, L. T., Moon, P. K., Gao, J., Thienemann, M., Forkert, N. D., Yeom, K. W. 2020; 3 (5): 1-15
  • Hypoferritinemia and iron deficiency in youth with pediatric acute-onset neuropsychiatric syndrome. Pediatric research Chan, A. n., Karpel, H. n., Spartz, E. n., Willett, T. n., Farhadian, B. n., Jeng, M. n., Thienemann, M. n., Frankovich, J. n. 2020

    Abstract

    Pediatric acute-onset neuropsychiatric syndrome (PANS) is an abrupt debilitating psychiatric illness. We anecdotally observed hypoferritinemia and iron deficiency in a subset of patients with PANS, prompting this study.In this IRB-approved prospective cohort study, we included patients seen at the Stanford PANS Clinic who met study criteria. The prevalence of hypoferritinemia (using cut-offs of 7 ng/ml in children ≤ 15 years and 18 ng/ml in adolescents > 15 years) and iron deficiency was estimated. Differences in patients with and without hypoferritinemia during PANS flare were explored.Seventy-nine subjects (mean age of PANS onset of 8.7 years) met study criteria. Hypoferritinemia was observed in 27% and three quarters occurred during a PANS flare. Compared to patients without hypoferritinemia during PANS flare, patients with hypoferritinemia had worse global impairment, more comorbid inflammatory diseases, and exhibited a chronic course of PANS illness. The estimated prevalence of iron deficiency was 3-8% in the PANS cohort, 1.4-2.0-fold higher than in the age- and sex-matched U.S.More stringent ferritin level cut-offs than the comparison CDC dataset were used.Hypoferritinemia and iron deficiency appear to be more common in PANS patients. More research is needed to confirm and understand this association.Our study suggests hypoferritinemia and iron deficiency are more common in patients with pediatric acute-onset neuropsychiatric syndrome (PANS) than in the sex- and age-matched US population.Hypoferritinemia was commonly observed during a disease flare but not associated with dietary or demographic factors. In patients with PANS and iron deficiency, clinicians should consider possibility of inflammation as the cause especially if iron deficiency cannot be explained by diet and blood loss.Future research should include larger cohorts to corroborate our study findings and consider examining the iron dynamics on MRI brain imaging in order to better understand the pathophysiology of PANS.

    View details for DOI 10.1038/s41390-020-1103-3

    View details for PubMedID 32746449

  • Association of Pediatric Acute-Onset Neuropsychiatric Syndrome With Microstructural Differences in Brain Regions Detected via Diffusion-Weighted Magnetic Resonance Imaging. JAMA network open Zheng, J. n., Frankovich, J. n., McKenna, E. S., Rowe, N. C., MacEachern, S. J., Ng, N. N., Tam, L. T., Moon, P. K., Gao, J. n., Thienemann, M. n., Forkert, N. D., Yeom, K. W. 2020; 3 (5): e204063

    Abstract

    Epidemiological studies indicate a link between obsessive-compulsive disorder and infections, particularly streptococcal pharyngitis. Pediatric acute-onset neuropsychiatric syndrome (PANS) manifests suddenly with obsessions, compulsions, and other behavioral disturbances, often after an infectious trigger. The current working model suggests a unifying inflammatory process involving the central nervous system, particularly the basal ganglia.To investigate whether diffusion-weighted magnetic resonance imaging (DWI) detects microstructural abnormalities across the brain regions of children with PANS.Case-control study performed at a single-center, multidisciplinary clinic in the United States focusing on the evaluation and treatment of children with PANS. Sixty consecutive patients who underwent 3 Tesla (T) magnetic resonance imaging (MRI) before immunomodulation from September 3, 2012, to March 30, 2018, were retrospectively reviewed for study inclusion. Six patients were excluded by blinded investigators because of imaging or motion artifacts, 3 patients for major pathologies, and 17 patients for suboptimal atlas image registration. In total, 34 patients with PANS before initiation of treatment were compared with 64 pediatric control participants.Using atlas-based MRI analysis, regional brain volume, diffusion, and cerebral blood flow were measured in the cerebral white matter, cerebral cortex, thalamus, caudate, putamen, pallidum, hippocampus, amygdala, nucleus accumbens, and brainstem. An age and sex-controlled multivariable analysis of covariance was used to compare patients with control participants.This study compared 34 patients with PANS (median age, 154 months; age range, 55-251 months; 17 girls and 17 boys) and 64 pediatric control participants (median age, 139 months; age range, 48-213 months); 41 girls and 23 boys). Multivariable analysis demonstrated a statistically significant difference in MRI parameters between patients with PANS and control participants (F21,74 = 6.91; P < .001; partial η2 = 0.662). All assessed brain regions had statistically significantly increased median diffusivity compared with 64 control participants. Specifically, the deep gray matter (eg, the thalamus, basal ganglia, and amygdala) demonstrated the most profound increases in diffusivity consistent with the cardinal clinical symptoms of obsessions, compulsions, emotional dysregulation, and sleep disturbances. No statistically significant differences were found regarding volume and cerebral blood flow.This study identifies cerebral microstructural differences in children with PANS in multiple brain structures, including the deep gray matter structures (eg, the thalamus, basal ganglia, and amygdala). Further study of MRI is warranted in prospective, clinical trials as a potential quantitative method for assessing patients under evaluation for PANS.

    View details for DOI 10.1001/jamanetworkopen.2020.4063

    View details for PubMedID 32364596

  • Infections, Antibiotics, and Mental Health Deteriorations. Journal of child and adolescent psychopharmacology Chan, A., Frankovich, J. 2019

    View details for DOI 10.1089/cap.2019.0100

    View details for PubMedID 31355667

  • Psychotic symptoms in youth with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) may reflect syndrome severity and heterogeneity (vol 110, pg 93, 2019) JOURNAL OF PSYCHIATRIC RESEARCH Silverman, M., Frankovich, J., Nguyen, E., Leibold, C., Yoon, J., Freeman, G., Karpel, H., Thienemann, M. 2019; 113: 45
  • The Burden of Caring for a Child or Adolescent With Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): An Observational Longitudinal Study JOURNAL OF CLINICAL PSYCHIATRY Frankovich, J., Leibold, C., Farmer, C., Sainani, K., Kamalani, G., Farhadian, B., Willett, T., Park, J. M., Sidell, D., Ahmed, S., Thienemann, M. 2019; 80 (1)
  • The Burden of Caring for a Child or Adolescent With Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): An Observational Longitudinal Study. The Journal of clinical psychiatry Frankovich, J., Leibold, C. M., Farmer, C., Sainani, K., Kamalani, G., Farhadian, B., Willett, T., Park, J. M., Sidell, D., Ahmed, S., Thienemann, M. 2018; 80 (1)

    Abstract

    OBJECTIVE: To describe the longitudinal association between disease severity, time established in clinical treatment, and caregiver burden in a community-based patient population diagnosed with pediatric acute-onset neuropsychiatric syndrome (PANS).METHODS: The study included an observational longitudinal cohort design, with Caregiver Burden Inventories (CBIs) collected between April 2013 and November 2016 at the Stanford PANS multidisciplinary clinic. Inclusion criteria for this study were as follows: pediatric patients meeting strict PANS/pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) diagnostic criteria (n = 187), having a caregiver fill out at least 1 complete CBI during a disease flare (n = 114); and having family who lives locally (n = 97). For longitudinal analyses, only patients whose caregiver had filled out 2 or more CBIs (n = 94 with 892 CBIs) were included. In the study sample, most primary caregivers were mothers (69 [71.1%] of 97), the majority of PANS patients were male (58 [59.8%] of 97), and mean age at PANS onset was 8.8 years.RESULTS: In a patient's first flare tracked by the clinic, 50% of caregivers exceeded the caregiver burden score threshold used to determine respite need in care receiver adult populations. Longitudinally, flares, compared with quiescence, predicted increases in mean CBI score (6.6 points; 95% CI, 5.1 to 8.0). Each year established in clinic predicted decreased CBI score (-3.5 points per year; 95% CI, -2.3 to -4.6). Also, shorter time between PANS onset and entry into the multidisciplinary clinic predicted greater improvement in mean CBI score over time (0.7 points per year squared; 95% CI, 0.1 to 1.3). Time between PANS onset and treatment with antibiotics or immunomodulation did not moderate the relationship between CBI score and time in clinic.CONCLUSIONS: PANS caregivers suffer high caregiver burden. Neuropsychiatric disease severity predicts increased caregiver burden. Caregiver burden tends to decrease over time in a group of patients undergoing clinical treatment at a specialty PANS clinic. This decrease could be independent of clinical treatment.

    View details for PubMedID 30549499

  • Psychotic symptoms in youth with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) may reflect syndrome severity and heterogeneity. Journal of psychiatric research Silverman, M., Frankovich, J., Nguyen, E., Leibold, C., Yoon, J., Mark Freeman, G. J., Karpel, H., Thienemann, M. 2018; 110: 93–102

    Abstract

    OBJECTIVE: In the clinical syndrome Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), obsessive compulsive disorder (OCD) and/or food refusal symptoms have an abrupt-onset (over 48 h) coupled with at least two other specified neuropsychiatric symptoms. We aimed to characterize in detail for the first time, psychotic symptoms experienced by children with PANS as well as the impact of psychotic symptoms on disease severity and course of illness. We inform about the diagnosis of the clinical description: PANS and hope to improve evaluation, treatment, diagnostic validity and future investigation.METHODS: Retrospective review of 143 consecutive PANS clinic patient charts meeting inclusion criteria. The Caregiver Burden Inventory, Global Impairment Score, and Children's Global Assessment Scale were used to assess impairment.RESULTS: Visual and auditory hallucinations were each experienced by 36%, of which most (83%) were transient and complex (non-threatening voices or figures). 6.3% and 5.5% of patients experienced delusions and thought disorganization respectively. Those with psychotic symptoms showed statistically significant differences in disease impairment and caregiver burden. There were no differences in time to treatment access or length of illness.CONCLUSIONS: Over 1/3 of children with PANS experienced transient hallucinations. They were more impaired than those without psychotic symptoms, but showed no differences in disease progression. This difference may point toward heterogeneity in PANS. When evaluating children with acute psychotic symptoms, clinicians should screen for abrupt-onset of a symptom cluster including OCD and/or food refusal, with neuropsychiatric symptoms (enuresis, handwriting changes, tics, hyperactivity, sleep disorder) before initiating treatment.

    View details for PubMedID 30605785

  • Psychometric Properties of the Pediatric Acute-Onset Neuropsychiatric Syndrome Global Impairment Score in Children and Adolescents with Pediatric Acute-Onset Neuropsychiatric Syndrome. Journal of child and adolescent psychopharmacology Leibold, C., Thienemann, M., Farhadian, B., Willett, T., Frankovich, J. 2018

    Abstract

    OBJECTIVES: This study validates the caregiver-rated Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) Global Impairment Score (GIS), a single-item, 0-100 scale, for use in PANS.METHODS: We collected longitudinal data from community patients meeting PANS criteria. We included 128 patients with 1926 GISs, each from a unique clinic visit. To assess discriminant validity, we compared GISs from patients with PANS with scores from a population of healthy controls. To evaluate external validity, we compared global impairment with a clinician-reported global measure-the Child Global Assessment Scale (CGAS)-using the Bland-Altman plots and correlation coefficients. Then, we evaluated associations between the PANS GIS and symptom-specific disease severity variables by fitting mixed models with repeated measures.RESULTS: The GIS shows excellent discriminant validity, distinguishing patients with PANS from healthy controls. The scores on the GIS show an acceptable level of agreement with the clinician-reported CGAS. The regression line in the Bland-Altman plot had a positive slope, indicating that parents tend to report higher disease severity than clinicians at higher levels of disease severity. Correlation was higher during disease remissions than during disease flares (r=-0.69 vs. r=-0.48). All disease severity scales predicted GIS in the expected direction.CONCLUSION: The GIS has excellent discriminant validity and acceptable construct validity.

    View details for PubMedID 30421965

  • Allergic Diseases and Immune-Mediated Food Disorders in Pediatric Acute-Onset Neuropsychiatric Syndrome. Pediatric allergy, immunology, and pulmonology Rosa, J. S., Hernandez, J. D., Sherr, J. A., Smith, B. M., Brown, K. D., Farhadian, B., Mahony, T., McGhee, S. A., Lewis, D. B., Thienemann, M., Frankovich, J. D. 2018; 31 (3): 158-165

    Abstract

    Background: The prevalence and impact of allergic and immune-mediated food disorders in pediatric acute-onset neuropsychiatric syndrome (PANS) are mostly unknown. Objective: We sought to explore the prevalence of atopic dermatitis (AD), asthma, allergic rhinitis (AR), IgE-mediated food allergies (FAs), and other immune-mediated food disorders requiring food avoidance in patients with PANS. In addition, to further understand the extent of food restriction in this population, we investigated the empiric use of dietary measures to improve PANS symptoms. Methods: Pediatric patients in a PANS Clinic and Research Program were given surveys regarding their caregiver burdens, allergic and food-related medical history, and whether food elimination resulted in perception of improvement of PANS symptoms. A review of health records was conducted to confirm that all responses in the survey were concordant with documentation of each patient's medical chart. Results: Sixty-nine (ages 4-20 years) of 80 subjects who fulfilled PANS criteria completed the surveys. Thirteen (18.8%) had AD, 11 (15.9%) asthma, 33 (47.8%) AR, 11 (15.9%) FA, 1 (1.4%) eosinophilic gastrointestinal disorders, 1 (1.4%) food protein-induced enterocolitis syndrome, 3 (4.3%) milk protein-induced proctocolitis syndrome, and 3 (4.3%) celiac disease. Thirty subjects (43.5%) avoided foods due to PANS; elimination of gluten and dairy was most common and was associated with perceived improvement of PANS symptoms (by parents). This perceived improvement was not confirmed with objective data. Conclusions: The prevalence of allergic and immune-mediated food disorders in PANS is similar to the general population as reported in the literature, with the exception of AR that appears to be more prevalent in our PANS cohort. More research will be required to establish whether diet or allergies influence PANS symptoms.

    View details for DOI 10.1089/ped.2018.0888

    View details for PubMedID 30283713

    View details for PubMedCentralID PMC6154445

  • Continued Presence of Period Limb Movements During REM Sleep in Patients With Chronic Static Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Santoro, J. D., Frankovich, J., Bhargava, S. 2018; 14 (7): 1187–92

    Abstract

    STUDY OBJECTIVES: A major component of pediatric acute-onset neuropsychiatric syndrome (PANS) is disruption of sleep. These disturbances have been reported in the acute phase of diagnosis but it is unknown if these sleep disruptions persist, especially in patients with chronic static symptoms. This retrospective chart review sought to review polysomnography (PSG) tests of patients in whom PANS has been clinically diagnosed in order to assess sleep architecture, periodic limb movements, and presence of rapid eye movement (REM) sleep without atonia (RSWA) after a chronic static course of symptoms, which were refractory to immunomodulatory interventions.METHODS: Patients were retrospectively identified through the PANS clinic at our institution and had to have fully completed a PSG study and be younger than 18 years. PSG with video were reviewed and scored based on established criteria.RESULTS: We identified 9 patients who met inclusion criteria. The median time from presentation to PSG was 4 years. This study identified PSG-measured periodic limb movement index (PLMI) > 5 events/h in REM sleep in 7 of 9 patients. Two patients with elevated PLMI also demonstrated RSWA, although neither fit a clinical diagnosis of REM sleep behavior disorder. This cohort also demonstrated increased onset of REM sleep (median 134 minutes), insomnia (median total sleep time of 389 minutes), and decreased sleep efficiency (77%).CONCLUSIONS: This study identifies continued sleep disturbances in patients with refractory PANS symptoms several years after diagnosis and treatment. Continued sleep disturbances after presentation and treatment in patients with chronic static PANS may be a contributing factor in prolonged symptomatology of this disease process.

    View details for DOI 10.5664/jcsm.7222

    View details for PubMedID 29991427

  • Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part I-Psychiatric and Behavioral Interventions. Journal of child and adolescent psychopharmacology Thienemann, M., Murphy, T., Leckman, J., Shaw, R., Williams, K., Kapphahn, C., Frankovich, J., Geller, D., Bernstein, G., Chang, K., Elia, J., Swedo, S. 2017; 27 (7): 566-573

    Abstract

    This article outlines the consensus guidelines for symptomatic treatment for children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Syndrome Associated with Streptococcal Infection (PANDAS).Extant literature on behavioral, psychotherapeutic, and psychopharmacologic treatments for PANS and PANDAS was reviewed. Members of the PANS Research Consortium pooled their clinical experiences to find agreement on treatment of PANS and PANDAS symptoms.Current guidelines result from consensus among the Consortium members.While underlying infectious and inflammatory processes in PANS and PANDAS patients are treated, psychiatric and behavioral symptoms need simultaneous treatment to decrease suffering and improve adherence to therapeutic intervention. Psychological, behavioral, and psychopharmacologic interventions tailored to each child's presentation can provide symptom improvement and improve functioning during both the acute and chronic stages of illness. In general, typical evidence-based interventions are appropriate for the varied symptoms of PANS and PANDAS. Individual differences in expected response to psychotropic medication may require marked reduction of initial treatment dose. Antimicrobials and immunomodulatory therapies may be indicated, as discussed in Parts 2 and 3 of this guideline series.

    View details for DOI 10.1089/cap.2016.0145

    View details for PubMedID 28722481

    View details for PubMedCentralID PMC5610394

  • Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part II-Use of Immunomodulatory Therapies. Journal of child and adolescent psychopharmacology Frankovich, J., Swedo, S., Murphy, T., Dale, R. C., Agalliu, D., Williams, K., Daines, M., Hornig, M., Chugani, H., Sanger, T., Muscal, E., Pasternack, M., Cooperstock, M., Gans, H., Zhang, Y., Cunningham, M., Bernstein, G., Bromberg, R., Willett, T., Brown, K., Farhadian, B., Chang, K., Geller, D., Hernandez, J., Sherr, J., Shaw, R., Latimer, E., Leckman, J., Thienemann, M. 2017; 27 (7): 574-593

    Abstract

    Introduction: Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a clinically heterogeneous disorder with a number of different etiologies and disease mechanisms. Inflammatory and postinfectious autoimmune presentations of PANS occur frequently, with some clinical series documenting immune abnormalities in 75%-80% of patients. Thus, comprehensive treatment protocols must include immunological interventions, but their use should be reserved only for PANS cases in which the symptoms represent underlying neuroinflammation or postinfectious autoimmunity, as seen in the PANDAS subgroup (Pediatric Autoimmune Neuropsychiatric Disorders associated with Streptococcal infections). Methods: The PANS Research Consortium (PRC) immunomodulatory task force is comprised of immunologists, rheumatologists, neurologists, infectious disease experts, general pediatricians, psychiatrists, nurse practitioners, and basic scientists with expertise in neuroimmunology and PANS-related animal models. Preliminary treatment guidelines were created in the Spring of 2014 at the National Institute of Health and refined over the ensuing 2 years over conference calls and a shared web-based document. Seven pediatric mental health practitioners, with expertise in diagnosing and monitoring patients with PANS, were consulted to create categories in disease severity and critically review final recommendations. All authors played a role in creating these guidelines. The views of all authors were incorporated and all authors gave final approval of these guidelines. Results: Separate guidelines were created for the use of immunomodulatory therapies in PANS patients with (1) mild, (2) moderate-to-severe, and (3) extreme/life-threatening severity. For mildly impairing PANS, the most appropriate therapy may be "tincture of time" combined with cognitive behavioral therapy and other supportive therapies. If symptoms persist, nonsteroidal anti-inflammatory drugs and/or short oral corticosteroid bursts are recommended. For moderate-to-severe PANS, oral or intravenous corticosteroids may be sufficient. However, intravenous immunoglobulin (IVIG) is often the preferred treatment for these patients by most PRC members. For more severe or chronic presentations, prolonged corticosteroid courses (with taper) or repeated high-dose corticosteroids may be indicated. For PANS with extreme and life-threatening impairment, therapeutic plasma exchange is the first-line therapy given either alone or in combination with IVIG, high-dose intravenous corticosteroids, and/or rituximab. Conclusions: These recommendations will help guide the use of anti-inflammatory and immunomodulatory therapy in the treatment of PANS.

    View details for DOI 10.1089/cap.2016.0148

    View details for PubMedID 36358107

  • Palatal Petechiae in the Absence of Group A Streptococcus in Pediatric Patients with Acute-Onset Neuropsychiatric Deterioration: A Cohort Study. Journal of child and adolescent psychopharmacology Mahony, T., Sidell, D., Gans, H., Cooperstock, M., Brown, K., Cheung, J. M., Farhadian, B., Gustafson, M., Thienemann, M., Frankovich, J. 2017

    Abstract

    Palatal petechiae are 95% specific for streptococcal pharyngitis. Despite this, and despite prior research demonstrating that Group A Streptococcus (GAS) is a common antecedent to pediatric acute-onset neuropsychiatric syndrome (PANS) episodes, we anecdotally observed a low rate of documented GAS in patients with PANS and palatal petechiae. This retrospective chart review was conducted to formally report the rate of palatal petechiae and concurrent GAS in a cohort of patients with PANS and investigate other etiologic factors.The clinical notes of 112 patients seen at the Stanford PANS Clinic who met PANS research criteria were reviewed for mention of palatal petechiae. The medical records of patients who demonstrated palatal petechiae on physical examination were reviewed for signs of infection, a clinical history of trauma, and laboratory results that could indicate other causes of petechiae.Twenty-three patients had documented palatal petechiae on physical examination (ages 5-16, 13/23 [57%] male). Fifteen patients had a rapid GAS test and GAS culture in the Stanford PANS clinic, all with negative results. Evidence of recent GAS infection was found in 8/23 (32%) patients (elevated GAS titers [n = 6] or documentation of a positive rapid GAS test at another facility [n = 2]), one of whom also had potential herpes simplex virus (HSV) infection. One patient had potential HSV infection and recent palatal trauma. No patients had thrombocytopenia. 14/23 (61%) of patients with palatal petechiae had no discernable cause of petechiae. 10/19 (53%) of patients had antihistone antibodies.Despite the established relationship between palatal petechiae and GAS, no patient with palatal petechiae in our clinic tested positive for GAS and only 32% had evidence of recent GAS. Most did not have an identifiable cause for the palatal lesions. This finding suggests the potential for alternative causes of palatal petechiae or undetectable GAS in our patient population. The high prevalence of palatal petechiae without GAS infection suggests that the pathogenesis of PANS is multifactorial and may involve disruption or inflammation of the microvasculature. Additional research is needed to further elucidate these findings.

    View details for DOI 10.1089/cap.2016.0153

    View details for PubMedID 28387528

  • An Electronic Health Record Investigation of Lenticulostriate Vasculopathy Features. American journal of perinatology Frankovich, J., Egan, M., Mahony, T., Benitz, W., Shaw, G. 2017; 34 (3): 253-258

    Abstract

    Objective Lenticulostriate vasculopathy (LSV) is characterized by linear hyperechogenicities in the basal ganglia found on the head ultrasounds of infants. We reviewed electronic health records of infants with and without LSV to investigate whether physician dictations indicated symptoms which could reflect subtle basal ganglia injury. Study Design In a case-control study, we analyzed data from 46 infants with LSV and 127 controls. Infants were stratified between term and preterm birth. Odds ratios (ORs) and 95% confidence intervals were calculated for tone abnormalities, apnea, feeding difficulties, seizures, and movement abnormalities in the presence of LSV. Results Both term and preterm infants with LSV showed elevated risks for tone abnormalities (OR: 3.6 and 2.9, respectively). Term infants with LSV showed elevated risks for hypotonia (OR: 4.3), apnea (OR: 2.9), and feeding difficulties (OR: 4.1). Preterm infants with LSV showed elevated risks for truncal hypotonia (OR: 3.9) and hyperreflexia (OR: 3.9). Conclusion Our findings provide some evidence that LSV is associated with an increased risk of early signs of abnormal development, possibly relating to signs of subtle basal ganglia injury. Historically LSV has been considered incidental. The associations identified here suggest that LSV findings are worthy of further study.

    View details for DOI 10.1055/s-0036-1585417

    View details for PubMedID 27471823

  • Improvement of psychiatric symptoms in youth following resolution of sinusitis INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY Mahony, T., Sidell, D., Gans, H., Brown, K., Farhadian, B., Gustafson, M., Sherr, J., Thienemann, M., Frankovich, J. 2017; 92: 38-44

    Abstract

    Accumulating evidence supports a role for inflammation in psychiatric illness, and the onset or exacerbation of psychiatric symptoms may follow non-CNS infections. Here, we provide the first detailed description of obsessive-compulsive and related psychiatric symptoms arising concurrently with sinusitis.We reviewed the charts of 150 consecutive patients evaluated in our Pediatric Acute-onset Neuropsychiatric Syndromes clinic for documented sinusitis as defined by the American Academy of Pediatrics guidelines. Sinusitis treatments, sinonasal imaging, and neuropsychiatric symptoms before, during, and after sinusitis onset were noted. Patients were included in the final review if they had a clear diagnosis of isolated sinusitis (without concurrent illness and/or immunodeficiency), and were evaluated during an episode of sinusitis.10/150 (6.6%) patients had isolated sinusitis at the time of their neuropsychiatric deterioration. Eight patients received antibiotics to treat sinusitis, three of whom also received sinus surgery. Neuropsychiatric symptoms improved in all eight patients concurrent with resolution of sinusitis per parent report and clinician assessment. One patient did not follow through with recommended sinus surgery or antibiotics and her psychiatric symptoms persisted. One patient was lost to follow-up.Improvement of psychiatric symptoms correlated with resolution of sinus disease in this retrospective study. Identification, treatment, and resolution of underlying infections, including sinusitis, may have the potential to change the trajectory of some neuropsychiatric illnesses. Randomized clinical trials are needed.

    View details for DOI 10.1016/j.ijporl.2016.10.034

    View details for Web of Science ID 000393245100008

    View details for PubMedID 28012531

  • Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part I—Psychiatric and Behavioral Interventions Journal of Child and Adolescent Psychopharmacology Thienemann, M., Murphy, T., Leckman, J., Shaw, R., Williams, K., Kapphahn, C., Frankovich, J., Geller, D., Bernstein, G., Chang, K., Elia, J., Swedo, S. 2017; 27 (7): 566-573

    Abstract

    This article outlines the consensus guidelines for symptomatic treatment for children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Syndrome Associated with Streptococcal Infection (PANDAS).Extant literature on behavioral, psychotherapeutic, and psychopharmacologic treatments for PANS and PANDAS was reviewed. Members of the PANS Research Consortium pooled their clinical experiences to find agreement on treatment of PANS and PANDAS symptoms.Current guidelines result from consensus among the Consortium members.While underlying infectious and inflammatory processes in PANS and PANDAS patients are treated, psychiatric and behavioral symptoms need simultaneous treatment to decrease suffering and improve adherence to therapeutic intervention. Psychological, behavioral, and psychopharmacologic interventions tailored to each child's presentation can provide symptom improvement and improve functioning during both the acute and chronic stages of illness. In general, typical evidence-based interventions are appropriate for the varied symptoms of PANS and PANDAS. Individual differences in expected response to psychotropic medication may require marked reduction of initial treatment dose. Antimicrobials and immunomodulatory therapies may be indicated, as discussed in Parts 2 and 3 of this guideline series.

    View details for DOI 10.1089/cap.2016.0145

    View details for PubMedCentralID PMC5610394

  • Course of Neuropsychiatric Symptoms After Introduction and Removal of Nonsteroidal Anti-Inflammatory Drugs: A Pediatric Observational Study. Journal of child and adolescent psychopharmacology Spartz, E. J., Freeman, G. M., Brown, K. n., Farhadian, B. n., Thienemann, M. n., Frankovich, J. n. 2017; 27 (7): 652–59

    Abstract

    Accumulating evidence suggests that anti-inflammatory interventions can modulate neuropsychiatric symptoms. Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterized by an abrupt and dramatic onset of obsessive-compulsive (OC) symptoms and/or severely restrictive food intake and at least two coinciding, equally debilitating neuropsychiatric symptoms. When associated with group A Streptococcus, the syndrome is labeled Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS). Here, we describe the course of neuropsychiatric symptoms in patients diagnosed with PANS and PANDAS after introduction or removal of nonsteroidal anti-inflammatory drugs (NSAIDs).We reviewed the electronic medical records (EMR) of 218 consecutive patients evaluated in our Stanford PANS Clinic for patients who met strict PANS or PANDAS research criteria and received NSAIDs for arthritis, pain, and/or psychiatric symptoms. We describe neuropsychiatric symptoms that were noted in the EMR before, during, and after NSAIDs were introduced or removed as the sole change in pharmacologic treatment.Seventy-seven patients were included in the current study. Of the 52 trials in which NSAID addition was the sole change in treatment, 16 (31%) coincided with an improvement in patients' neuropsychiatric symptoms. Of the 57 trials in which removal of NSAID treatment was the sole change in treatment, 20 (35%) coincided with escalation in patients' neuropsychiatric symptoms. Thirty patients (39%) experienced side effects, mainly mild gastrointestinal symptoms, which self-resolved after removal of NSAID, reduction of dose, or change in NSAID.Improvement in neuropsychiatric symptoms was evident in roughly one-third of NSAID treatment trials. A randomized clinical trial will be necessary to confirm whether NSAIDs are successful in reducing neuropsychiatric symptoms in youth with PANS.

    View details for PubMedID 28696783

  • Effect of Early and Prophylactic Nonsteroidal Anti-Inflammatory Drugs on Flare Duration in Pediatric Acute-Onset Neuropsychiatric Syndrome: An Observational Study of Patients Followed by an Academic Community-Based Pediatric Acute-Onset Neuropsychiatric Syndrome Clinic. Journal of child and adolescent psychopharmacology Brown, K. D., Farmer, C. n., Freeman, G. M., Spartz, E. J., Farhadian, B. n., Thienemann, M. n., Frankovich, J. n. 2017; 27 (7): 619–28

    Abstract

    Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterized by the sudden onset of severe obsessive-compulsive symptoms and/or eating restriction along with at least two coinciding neuropsychiatric symptoms. When associated with group A Streptococcus, the syndrome is labeled Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS). An abnormal immune response to infection and subsequent neuroinflammation is postulated to play an etiologic role. We evaluated the impact of nonsteroidal anti-inflammatory drug (NSAID) treatment on flare duration in PANS/PANDAS.Patient inclusion criteria: Patients were included if they had at least one neuropsychiatric deterioration ("flare") that met strict PANS/PANDAS research criteria and for which flare duration could be assessed. Flare inclusion criteria: Any flare that started before October 15, 2016 was included and followed until the flare resolved or until the end of our data collection (November 1, 2016). Flare exclusion criteria: Flares were excluded if they were incompletely resolved, treated with aggressive immunomodulation, or treated with NSAIDs late (>30 days of flare onset). Ninety-five patients met study inclusion criteria and collectively experienced 390 flares that met flare criteria. Data were analyzed using multilevel linear models, adjusting for demographics, disease, and treatment covariates.NSAID use was associated with a significantly shorter flare duration. Flares not treated with NSAIDs had a mean duration of approximately 12.2 weeks (95% CI: 9.3-15.1). Flares that occurred while the child was on NSAID maintenance therapy were approximately 4 weeks shorter than flares not managed with NSAIDs (95% CI: 1.85-6.24; p < 0.0001). Flares treated with NSAIDs within 30 days of flare onset were approximately 2.6 weeks shorter than flares not managed with NSAIDs (95% CI: 0.43-4.68; p = 0.02). Flares treated prophylactically and those treated early with NSAIDs did not differ in duration (p = 0.26). Among the flares that received NSAID treatment within the first 30 days, earlier intervention was modestly associated with shorter flare durations (i.e., for each day that NSAID treatment was delayed, flare duration increased by 0.18 weeks; 95% CI: 0.03-0.33; p = 0.02), though it was not statistically significant after controlling for covariates (p = 0.06).NSAIDs given prophylactically or within 30 days of flare onset may shorten neuropsychiatric symptom duration in patients with new-onset and relapsing/remitting PANS and PANDAS. A randomized placebo-control clinical trial of NSAIDs in PANS is warranted to formally assess treatment efficacy.

    View details for PubMedID 28696786

  • Pediatric Acute-Onset Neuropsychiatric Syndrome Response to Oral Corticosteroid Bursts: An Observational Study of Patients in an Academic Community-Based PANS Clinic. Journal of child and adolescent psychopharmacology Brown, K. n., Farmer, C. n., Farhadian, B. n., Hernandez, J. n., Thienemann, M. n., Frankovich, J. n. 2017; 27 (7): 629–39

    Abstract

    Sudden-onset severe obsessive-compulsive symptoms and/or severely restrictive food intake with at least two coinciding, similarly debilitating neuropsychiatric symptoms define Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). When associated with Group A Streptococcus, the syndrome is labeled Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS). An abnormal immune response to infection and subsequent neuroinflammation is postulated to play an etiologic role. Most patients have a relapsing-remitting course. Treatment outcome data for youth with PANS and PANDAS are limited.One hundred seventy-eight consecutive patients were seen in the Stanford PANS clinic between September 1, 2012 and January 15, 2016, of whom 98 met PANS or PANDAS criteria, had a single episode of PANS or relapsing/remitting course, and collectively experienced 403 flares. Eighty-five flares were treated with 102 total courses of oral corticosteroids of either short (4-5 days) or long (5 days-8 weeks) duration. Response to treatment was assessed within 14 days of initiating a short burst of corticosteroids and at the end of a long burst based on clinician documentation and patient questionnaires. Data were analyzed by using multilevel random-effects models.Patients experienced shorter flares when treated with oral corticosteroids (6.4 ± 5.0 weeks vs. 11.4 ± 8.6 weeks) than when not treated (p < 0.001), even after controlling for presumed confounding variables, including age at flare, weeks since onset of PANS illness, sex, antibiotic treatment, prophylactic antibiotics, previous immunomodulatory treatment, maintenance anti-inflammatory therapy, psychiatric medications, and cognitive behavioral therapy (p < 0.01). When corticosteroids were given for the initial PANS episode, flares tended to be shorter (10.3 ± 5.7 weeks) than when not treated (16.5 ± 9.6 weeks) (p = 0.06). This difference was statistically significant after controlling for the relevant confounding variables listed earlier (p < 0.01). Earlier use of corticosteroids was associated with shorter flare durations (p < 0.001). Longer courses of corticosteroids were associated with a more enduring impact on the duration of neuropsychiatric symptom improvement (p = 0.014).Corticosteroids may be a helpful treatment intervention in patients with new-onset and relapsing/remitting PANS and PANDAS, hastening symptom improvement or resolution. When corticosteroids are given earlier in a disease flare, symptoms improve more quickly and patients achieve clinical remission sooner. Longer courses of corticosteroids may result in more durable remissions. A double-blind placebo-controlled clinical trial of corticosteroids in PANS is warranted to formally assess treatment efficacy.

    View details for PubMedID 28714753

  • Clinical Management of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS): Part II – Use of Immunomodulatory Therapies Journal of Child and Adolescent Psychopharmacology Frankovich, J., Swedo, S., Murphy, T., Dale, R. C., Agalliu, D., Williams, K., Daines, M., Hornig, M., Chugani, H., Sanger, T., Muscal, E., Pasternack, M., Cooperstock, M., Gans, H., Zhang, Y., Cunningham, M., Bernstein, G., Bromberg, R., Willett, T., Brown, K., Farhadian, B., Chang, K., Geller, D., Hernandez, J., Sherr, J., et al 2017; 27 (7): 574-593

    View details for DOI 10.1089/cap.2016.0148

  • Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Holzinger, D., Fassl, S. K., de Jager, W., Lohse, P., Roehrig, U. F., Gattorno, M., Omenetti, A., Chiesa, S., Schena, F., Austermann, J., Vogl, T., Kuhns, D. B., Holland, S. M., Rodriguez-Gallego, C., Lopez-Almaraz, R., Arostegui, J. I., Colino, E., Roldan, R., Fessatou, S., Isidor, B., Poignant, S., Ito, K., Epple, H., Bernstein, J. A., Jeng, M., Frankovich, J., Lionetti, G., Church, J. A., Ong, P. Y., LaPlant, M., Abinun, M., Skinner, R., Bigley, V., Sachs, U. J., Hinze, C., Hoppenreijs, E., Ehrchen, J., Foell, D., Chae, J. J., Ombrello, A., Aksentijevich, I., Sunderkoetter, C., Roth, J. 2015; 136 (5): 1337-1345

    Abstract

    Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving extremely high serum concentrations of the proinflammatory alarmin myeloid-related protein (MRP) 8/14 (S100A8/S100A9 and calprotectin).We sought to characterize the genetic cause and clinical spectrum of Hz/Hc.Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and their clinical phenotype was compared with that of 11 patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. PSTPIP1-pyrin interactions were analyzed by means of immunoprecipitation and Western blotting. A structural model of the PSTPIP1 dimer was generated. Cytokine profiles were analyzed by using the multiplex immunoassay, and MRP8/14 serum concentrations were analyzed by using an ELISA.Thirteen patients were heterozygous for a missense mutation in the PSTPIP1 gene, resulting in a p.E250K mutation, and 1 carried a mutation resulting in p.E257K. Both mutations substantially alter the electrostatic potential of the PSTPIP1 dimer model in a region critical for protein-protein interaction. Patients with Hz/Hc have extremely high MRP8/14 concentrations (2045 ± 1300 μg/mL) compared with those with PAPA syndrome (116 ± 74 μg/mL) and have a distinct clinical phenotype. A specific cytokine profile is associated with Hz/Hc. Hz/Hc mutations altered protein binding of PSTPIP1, increasing interaction with pyrin through phosphorylation of PSTPIP1.Mutations resulting in charge reversal in the y-domain of PSTPIP1 (E→K) and increased interaction with pyrin cause a distinct autoinflammatory disorder defined by clinical and biochemical features not found in patients with PAPA syndrome, indicating a unique genotype-phenotype correlation for mutations in the PSTPIP1 gene. This is the first inborn autoinflammatory syndrome in which inflammation is driven by uncontrolled release of members of the alarmin family.

    View details for DOI 10.1016/j.jaci.2015.04.016

    View details for PubMedID 26025129

  • Multidisciplinary clinic dedicated to treating youth with pediatric acute-onset neuropsychiatric syndrome: presenting characteristics of the first 47 consecutive patients. Journal of child and adolescent psychopharmacology Frankovich, J., Thienemann, M., Pearlstein, J., Crable, A., Brown, K., Chang, K. 2015; 25 (1): 38-47

    Abstract

    Abrupt, dramatic onset obsessive-compulsive disorder (OCD) and/or eating restriction with at least two coinciding symptoms (anxiety, mood dysregulation, irritability/aggression/oppositionality, behavioral regression, cognitive deterioration, sensory or motor abnormalities, or somatic symptoms) defines pediatric acute-onset neuropsychiatric syndrome (PANS). Descriptions of clinical data in such youth are limited.We reviewed charts of 53 consecutive patients evaluated in our PANS Clinic; 47 met PANS symptom criteria but not all met the requirement for "acute onset." Patients meeting full criteria for PANS were compared with patients who had a subacute/insidious onset of symptoms.Nineteen of 47 (40%) patients in the study had acute onset of symptoms. In these patients, autoimmune/inflammatory diseases and psychiatric disorders were common in first-degree family members (71% and 78%, respectively). Most acute-onset patients had a relapsing/remitting course (84%), prominent sleep disturbances (84%), urinary issues (58%), sensory amplification (66%), gastrointestinal symptoms (42%), and generalized pain (68%). Inflammatory back pain (21%) and other arthritis conditions (28%) were also common. Suicidal and homicidal thoughts and gestures were common (44% and 17%, respectively) as were violent outbursts (61%). Group A streptococcus (GAS) was the most commonly identified infection at onset (21%) and during flares (74%). Rates of the abovementioned characteristics did not differ between the acute-onset group and the subacute/insidious-onset groups. Low levels of immunoglobulins were more common in the subacute/insidious-onset group (75%) compared with the acute-onset group (22%), but this was not statistically significant (p=0.06).In our PANS clinic, 40% of patients had acute onset of symptoms. However, those with and without acute onset of symptoms had similar symptom presentation, rates of inflammatory conditions, somatic symptoms, and violent thoughts and behaviors. GAS infections were the most commonly identified infection at onset and at symptom flares. Because of the wide variety of medical and psychiatric symptoms, youth with PANS may require a multidisciplinary team for adequate care management.

    View details for DOI 10.1089/cap.2014.0081

    View details for PubMedID 25695943

  • Five youth with pediatric acute-onset neuropsychiatric syndrome of differing etiologies. Journal of child and adolescent psychopharmacology Frankovich, J., Thienemann, M., Rana, S., Chang, K. 2015; 25 (1): 31-37

    Abstract

    Pediatric acute-onset neuropsychiatric syndrome (PANS) is diagnosed by the abrupt onset of new obsessive compulsive disorder (OCD) or food-restricting symptoms, and at least two of a variety of other neuropsychiatric symptoms. Detailed clinical presentation of youth with this condition has not yet been provided in the literature.We review the clinical charts of five youth meeting criteria for PANS in our PANS Clinic. These five patients were selected for differing underlying causes thought to be driving an inflammatory response that appeared to impact psychiatric symptoms.Five youth with varying potential etiologies impacting neuropsychiatric symptoms were identified. These youth were from 8 to 18 years old at the onset of their PANS illness, and had bacterial, autoimmune, and unknown etiologies. Treatment directed at presumed etiologies ranged from antibiotics to intravenous gamma globulin (IVIG) to other immunomodulatory regimens, and appeared to improve the psychiatric illness.Youth with PANS may present in differing ways, with psychiatric and physical symptoms overlapping with inflammatory or infectious diseases, pain syndromes, and other psychiatric diagnoses. Patients' psychiatric symptoms may respond to treatments targeting the underlying cause of physical illness. Faced with a pediatric patient demonstrating the abrupt onset or exacerbation of psychiatric and physical symptoms, clinicians should consider PANS in their differential diagnosis.

    View details for DOI 10.1089/cap.2014.0056

    View details for PubMedID 25695942

  • Clinical Evaluation of Youth with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): Recommendations from the 2013 PANS Consensus Conference. Journal of child and adolescent psychopharmacology Chang, K., Frankovich, J., Cooperstock, M., Cunningham, M. W., Latimer, M. E., Murphy, T. K., Pasternack, M., Thienemann, M., Williams, K., Walter, J., Swedo, S. E. 2015; 25 (1): 3-13

    Abstract

    On May 23 and 24, 2013, the First PANS Consensus Conference was convened at Stanford University, calling together a geographically diverse group of clinicians and researchers from complementary fields of pediatrics: General and developmental pediatrics, infectious diseases, immunology, rheumatology, neurology, and child psychiatry. Participants were academicians with clinical and research interests in pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS) in youth, and the larger category of pediatric acute-onset neuropsychiatric syndrome (PANS). The goals were to clarify the diagnostic boundaries of PANS, to develop systematic strategies for evaluation of suspected PANS cases, and to set forth the most urgently needed studies in this field. Presented here is a consensus statement proposing recommendations for the diagnostic evaluation of youth presenting with PANS.

    View details for DOI 10.1089/cap.2014.0084

    View details for PubMedID 25325534

  • Pediatric plastic bronchitis: case report and retrospective comparative analysis of epidemiology and pathology. Case reports in pulmonology Kunder, R., Kunder, C., Sun, H. Y., Berry, G., Messner, A., Frankovich, J., Roth, S., Mark, J. 2013; 2013: 649365-?

    Abstract

    Plastic bronchitis (PB) is a pathologic condition in which airway casts develop in the tracheobronchial tree causing airway obstruction. There is no standard treatment strategy for this uncommon condition. We report an index patient treated using an emerging multimodal strategy of directly instilled and inhaled tissue plasminogen activator (t-PA) as well as 13 other cases of PB at our institution between 2000 and 2012. The majority of cases (n = 8) occurred in patients with congenital heart disease. Clinical presentations, treatments used, histopathology of the casts, and patient outcomes are reviewed. Further discussion is focused on the epidemiology of plastic bronchitis and a systematic approach to the histologic classification of casts. Comorbid conditions identified in this study included congenital heart disease (8), pneumonia (3), and asthma (2). Our institutional prevalence rate was 6.8 per 100,000 patients, and our case fatality rate was 7%.

    View details for DOI 10.1155/2013/649365

    View details for PubMedID 23662235

  • Profiling risk factors for chronic uveitis in juvenile idiopathic arthritis: a new model for EHR-based research. Pediatric rheumatology online journal Cole, T. S., Frankovich, J., Iyer, S., LePendu, P., Bauer-Mehren, A., Shah, N. H. 2013; 11 (1): 45-?

    Abstract

    Juvenile idiopathic arthritis is the most common rheumatic disease in children. Chronic uveitis is a common and serious comorbid condition of juvenile idiopathic arthritis, with insidious presentation and potential to cause blindness. Knowledge of clinical associations will improve risk stratification. Based on clinical observation, we hypothesized that allergic conditions are associated with chronic uveitis in juvenile idiopathic arthritis patients.This study is a retrospective cohort study using Stanford's clinical data warehouse containing data from Lucile Packard Children's Hospital from 2000-2011 to analyze patient characteristics associated with chronic uveitis in a large juvenile idiopathic arthritis cohort. Clinical notes in patients under 16 years of age were processed via a validated text analytics pipeline. Bivariate-associated variables were used in a multivariate logistic regression adjusted for age, gender, and race. Previously reported associations were evaluated to validate our methods. The main outcome measure was presence of terms indicating allergy or allergy medications use overrepresented in juvenile idiopathic arthritis patients with chronic uveitis. Residual text features were then used in unsupervised hierarchical clustering to compare clinical text similarity between patients with and without uveitis.Previously reported associations with uveitis in juvenile idiopathic arthritis patients (earlier age at arthritis diagnosis, oligoarticular-onset disease, antinuclear antibody status, history of psoriasis) were reproduced in our study. Use of allergy medications and terms describing allergic conditions were independently associated with chronic uveitis. The association with allergy drugs when adjusted for known associations remained significant (OR 2.54, 95% CI 1.22-5.4).This study shows the potential of using a validated text analytics pipeline on clinical data warehouses to examine practice-based evidence for evaluating hypotheses formed during patient care. Our study reproduces four known associations with uveitis development in juvenile idiopathic arthritis patients, and reports a new association between allergic conditions and chronic uveitis in juvenile idiopathic arthritis patients.

    View details for DOI 10.1186/1546-0096-11-45

    View details for PubMedID 24299016

  • European ancestry decreases the risk of early onset, severe lupus nephritis in a single center, multiethnic pediatric lupus inception cohort LUPUS Frankovich, J. D., Hsu, J. J., Sandborg, C. I. 2012; 21 (4): 421-429

    Abstract

    To determine whether pediatric SLE patients without European ancestry are at higher risk for development of severe lupus nephritis (ISN/RPS class III, IV or V).Ninety-eight of 101 patients with pediatric SLE (age <18 years at diagnosis) were enrolled. Race/ethnicity of four grandparents, socioeconomic status (SES) and language proficiency were collected. The primary outcome was time to development of severe lupus nephritis.Based on patient report of four grandparent ancestry, 29% had at least one grandparent of European ancestry (14% had all four grandparents of European ancestry). Patients without European ancestry were 46% Hispanic, 47% Asian, and 3% African American. In the entire 98 patient cohort, 12% had ≥3 different ancestries. Patients without European ancestry had significantly lower SES levels and English proficiency. There was no significant difference between patients with or without European ancestry in duration of SLE, age of onset, and lag time between symptoms and diagnosis. Patients with at least one grandparent of European ancestry had a decreased risk of developing severe lupus nephritis, which remained significant after controlling for age, gender, SES and English proficiency (hazard ratio 0.4, 95% confidence interval 0.2-0.9).This study demonstrates that presence of at least one grandparent of European ancestry decreases the risk of severe lupus nephritis, a finding that is not explained by measurable socioeconomic differences and language barriers.

    View details for DOI 10.1177/0961203312437805

    View details for PubMedID 22427363

  • Evidence-Based Medicine in the EMR Era NEW ENGLAND JOURNAL OF MEDICINE Frankovich, J., Longhurst, C. A., Sutherland, S. M. 2011; 365 (19): 1758-1759

    View details for DOI 10.1056/NEJMp1108726

    View details for Web of Science ID 000296762800003

    View details for PubMedID 22047518

  • Autoinflammatory Diseases in the Neonate: Mimickers of Neonatal Infections NeoReviews Lionetti, G., Lapidus, S., Goldbach-Mansky, R., Frankovich, J. 2010; 11 (10): e566-e577

    View details for DOI 10.1542/neo.11-10-e566

  • Acute hepatitis in three patients with systemic juvenile idiopathic arthritis taking interleukin-1 receptor antagonist PEDIATRIC RHEUMATOLOGY Canna, S., Frankovich, J., Higgins, G., Narkewicz, M. R., Nash, S. R., Hollister, J. R., Soep, J. B., Dragone, L. L. 2009; 7

    Abstract

    We investigated the etiology of acute hepatitis in three children with systemic Juvenile Idiopathic Arthritis (sJIA) taking Interleukin-1 receptor antagonist (IL1RA).Laboratory and clinical data for three children with sJIA diagnosed at ages 13 months to 8 years who developed acute hepatitis during treatment with IL1RA were reviewed for evidence of sJIA flare, infection, macrophage activation syndrome (MAS), malignancy, and drug reaction.In all patients, hepatitis persisted despite cessation of known hepatotoxic drugs and in absence of known infectious triggers, until discontinuation of IL1RA. Liver biopsies had mixed inflammatory infiltrates with associated hepatocellular injury suggestive of an exogenous trigger. At the time of hepatitis, laboratory data and liver biopsies were not characteristic of MAS. In two patients, transaminitis resolved within one week of discontinuing IL1RA, the third improved dramatically in one month.Although sJIA symptoms improved significantly on IL1RA, it appeared that IL1RA contributed to the development of acute hepatitis. Hepatitis possibly occurred as a result of an altered immune response to a typical childhood infection while on IL1RA. Alternatively, hepatitis could have represented an atypical presentation of MAS in patients with sJIA taking IL1RA. Further investigation is warranted to determine how anti-IL1 therapies alter immune responsiveness to exogenous triggers in patients with immune dysfunction such as sJIA. Our patients suggest that close monitoring for hepatic and other toxicities is indicated when treating with IL1RA.

    View details for DOI 10.1186/1546-0096-7-21

    View details for Web of Science ID 000273814800001

    View details for PubMedID 20028520

    View details for PubMedCentralID PMC2805658

  • Neonatal Lupus and Related Autoimmune Disorders of Infants NeoReviews Frankovich, J., Sandborg, C., Barnes, P., Hintz, S., Chakravarty, E. 2008; 9 (5): e206-e217

    View details for DOI 10.1542/neo.9-5-e206

  • IMMUNOPHENOTYPING DATA IN PANS Frankovich, J. ELSEVIER SCIENCE INC. 2023: S393
  • PANS: MARKERS OF INFLAMMATION/AUTOIMMUNITY AT CLINICAL PRESENTATION AND EVENTUAL DEVELOPMENT OF ARTHRITIS AND OTHER AUTOIMMUNE DISEASES Ma, M., Masterson, E., Frankovich, J. ELSEVIER SCIENCE INC. 2023: S275
  • ANTIDOPAMINE RECEPTOR AUTOANTIBODY DETECTION IN POSTINFECTIOUS NEUROPSYCHIATRIC SYNDROMES Yin, X., Prestwood, T., Utz, P. J., Frankovich, J. ELSEVIER SCIENCE INC. 2023: S273
  • Post-infectious inflammation, autoimmunity, and OCD: Sydenham Chorea, Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS), and Pediatric Acute-onset Neuropsychiatric Disorder (PANS) DEVELOPMENTAL NEUROSCIENCE Vreeland, A., Calaprice, D., Or-Geva, N., Frye, R. E., Agalliu, D., Lachman, H. M., Pittenger, C., Pallanti, S., Williams, K., Ma, M., Thienemann, M., Gagliano, A., Mellins, E., Frankovich, J. 2023

    Abstract

    Post-infectious neuroinflammation has been implicated in multiple models of acute onset obsessive-compulsive disorder (OCD) including Sydenham's chorea (SC), pediatric acute-onset neuropsychiatric syndrome (PANS), and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). These conditions are associated with a range of autoantibodies which are thought to be triggered by an infections, most notably group A streptococci (GAS). Based on animal models using huma sera, these autoantibodies are thought to cross-react with neural antigens in the basal ganglia and modulate neuronal activity and behavior. As is true for many childhood neuroinflammatory diseases and rheumatological diseases, SC, PANS, and PANDAS lack clinically available, rigorous diagnostic biomarkers and randomized clinical trials. In this review article, we outline the accumulating evidence supporting the role neuroinflammation plays in these disorders. We describe work with animal models including patient-derived anti-neuronal autoantibodies, and we outline imaging studies that show alterations in the basal ganglia. In addition, we present research on metabolites, which are helpful in deciphering functional phenotypes, and on the implication of sleep in these disorders. Finally, we encourage future researchers to collaborate across medical specialties (e.g., pediatrics, psychiatry, rheumatology, immunology, and infectious disease) in order to further research on clinical syndromes presenting with neuropsychiatric manifestations.

    View details for DOI 10.1159/000534261

    View details for Web of Science ID 001076907900001

    View details for PubMedID 37742615

  • Evaluation of C4 gene copy number in Pediatric Acute Neuropsychiatric Syndrome DEVELOPMENTAL NEUROSCIENCE Kalinowski, A., Tian, L., Pattni, R., Ollila, H., Khan, M., Manko, C., Silverman, M., Ma, M., Columbo, L., Farhadian, B., Swedo, S., Murphy, T., Johnson, M., Fernell, E., Gillberg, C., Thienemann, M., Mellins, E. D., Levinson, D. F., Urban, A. E., Frankovich, J. 2023

    Abstract

    Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is an abrupt-onset neuropsychiatric disorder. PANS patients have an increased prevalence of co-morbid autoimmune illness, most commonly arthritis. In addition, an estimated one-third of PANS patients present with low serum C4 protein, suggesting decreased production or increased consumption of C4 protein. To test the possibility that copy number (CN) variation contributes to risk of PANS illness, we compared mean total C4A and total C4B CN in ethnically-matched subjects from PANS DNA samples and controls (192 cases and 182 controls). Longitudinal data from the Stanford PANS cohort (n = 121) was used to assess whether the time to Juvenile Idiopathic Arthritis (JIA) or Autoimmune Disease (AI) onset was a function of total C4A or C4B. Lastly, we performed several hypothesis-generating analyses to explore the correlation between individual C4 gene variants, sex, specific genotypes and age of PANS onset. Although the mean total C4A or C4B CN did not differ in PANS compared to controls, PANS patients with low C4B CN were at increased risk for subsequent JIA diagnosis (Hazard Ratio = 27, p-value = 0004). We also observed a possible increase in risk for AI in PANS patients and a possible correlation between lower C4B and PANS age of onset. An association between rheumatoid arthritis and low C4B CN has been reported previously. However, patients with PANS develop different types of JIA: enthesitis-related arthritis, spondyloarthritis and psoriatic arthritis. This suggests that C4B plays a role that spans these arthritis types.

    View details for DOI 10.1159/000531707

    View details for Web of Science ID 001018232500001

    View details for PubMedID 37379808

  • Neuroinflammation in Obsessive-Compulsive Disorder: Sydenham Chorea, Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections, and Pediatric Acute Onset Neuropsychiatric Syndrome. The Psychiatric clinics of North America Vreeland, A., Thienemann, M., Cunningham, M., Muscal, E., Pittenger, C., Frankovich, J. 2023; 46 (1): 69-88

    Abstract

    Sydenham chorea (SC), pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS) are postinfectious neuroinflammatory diseases that involve the basal ganglia and have obsessive-compulsive disorder as a major manifestation. As is true for many childhood rheumatological diseases and neuroinflammatory diseases, SC, PANDAS and PANS lack clinically available, rigorous diagnostic biomarkers and randomized clinical trials. Research on the treatment of these disorders depend on three complementary modes of intervention including: treating the symptoms, treating the source of inflammation, and treating disturbances of the immune system. Future studies should aim to integrate neuroimaging, inflammation, immunogenetic, and clinical data (noting the stage in the clinical course) to increase our understanding and treatment of SC, PANDAS, PANS, and all other postinfectious/immune-mediated behavioral disorders.

    View details for DOI 10.1016/j.psc.2022.11.004

    View details for PubMedID 36740356

  • Autoantibodies are highly prevalent in non-SARS-CoV-2 respiratory infections and critical illness. JCI insight Feng, A., Yang, E. Y., Moore, A. R., Dhingra, S., Chang, S. E., Yin, X., Pi, R., Mack, E. K., Völkel, S., Geßner, R., Gündisch, M., Neubauer, A., Renz, H., Tsiodras, S., Fragkou, P. C., Asuni, A. A., Levitt, J. E., Wilson, J. G., Leong, M., Lumb, J. H., Mao, R., Pinedo, K., Roque, J., Richards, C. M., Stabile, M., Swaminathan, G., Salagianni, M. L., Triantafyllia, V., Bertrams, W., Blish, C. A., Carette, J. E., Frankovich, J., Meffre, E., Nadeau, K. C., Singh, U., Wang, T. T., Luning Prak, E. T., Herold, S., Andreakos, E., Schmeck, B., Skevaki, C., Rogers, A. J., Utz, P. J. 2023; 8 (3)

    Abstract

    The widespread presence of autoantibodies in acute infection with SARS-CoV-2 is increasingly recognized, but the prevalence of autoantibodies in non-SARS-CoV-2 infections and critical illness has not yet been reported. We profiled IgG autoantibodies in 267 patients from 5 independent cohorts with non-SARS-CoV-2 viral, bacterial, and noninfectious critical illness. Serum samples were screened using Luminex arrays that included 58 cytokines and 55 autoantigens, many of which are associated with connective tissue diseases (CTDs). Samples positive for anti-cytokine antibodies were tested for receptor blocking activity using cell-based functional assays. Anti-cytokine antibodies were identified in > 50% of patients across all 5 acutely ill cohorts. In critically ill patients, anti-cytokine antibodies were far more common in infected versus uninfected patients. In cell-based functional assays, 11 of 39 samples positive for select anti-cytokine antibodies displayed receptor blocking activity against surface receptors for Type I IFN, GM-CSF, and IL-6. Autoantibodies against CTD-associated autoantigens were also commonly observed, including newly detected antibodies that emerged in longitudinal samples. These findings demonstrate that anti-cytokine and autoantibodies are common across different viral and nonviral infections and range in severity of illness.

    View details for DOI 10.1172/jci.insight.163150

    View details for PubMedID 36752204

  • Group Psychotherapy for Parents of Youth with Pediatric Acute-Onset Neuropsychiatric Syndrome. Journal of clinical psychology in medical settings Ellerkamp, H., Thienemann, M., Tinero, J., Shaw, R., Dowtin, L. L., Frankovich, J., Borkovi, T. C. 2022

    Abstract

    Parents of children with diagnoses of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS) may experience significant psychological distress related to their child's severe and relapsing illness and challenges with the traumatic nature of its treatment. No manualized or studied psychological interventions specifically for parents of youth with PANS have existed prior to this study. In this pilot study, we assessed the feasibility, satisfaction, and treatment fidelity of a brief 9-session group therapy intervention for parents based on principles of trauma-focused cognitive behavior therapy (CBT). We hypothesized that, if initially elevated, symptoms of depression, anxiety, and trauma would decrease and participants' utilization of positive coping mechanisms would increase post-intervention. We adapted an existing evidence-based group intervention developed for parents of children with premature infants to target sources of stress and coping in parents of children with PANS. Ten parents participated in the study. The 9-session intervention used a combination of techniques that included cognitive restructuring, coping skills, self-care, and a trauma narrative to address psychological stress, trust, grief, and unwanted emotions. Outcome measures included parental symptoms of anxiety, depression, and posttraumatic stress disorder (PTSD), as well as rating of parental satisfaction with the intervention. The treatment was feasible and deliverable with high fidelity. The intervention was rated as useful and satisfactory by parents (overall average usefulness of 4.54 and satisfaction of 4.71 out of 5.0). Elevated symptoms of PTSD and depression decreased with large effect sizes (Cohen's d = 1.42 and Cohen's d = 1.38, respectively). Participating parents demonstrated significantly more active coping and acceptance behaviors and stances. A brief 9-session group therapy intervention based on principles of trauma-focused CBT was found to be effective in reducing symptoms of psychological distress in parents of children with PANS.

    View details for DOI 10.1007/s10880-022-09926-0

    View details for PubMedID 36480109

  • Autoantibodies targeting cytokines and connective tissue disease autoantigens are common in acute non-SARS-CoV-2 infections. Research square Feng, A., Yang, E., Moore, A., Dhingra, S., Chang, S., Yin, X., Pi, R., Mack, E., Völkel, S., Geßner, R., Gundisch, M., Neubauer, A., Renz, H., Tsiodras, S., Fragkou, P., Asuni, A., Levitt, J., Wilson, J., Leong, M., Lumb, J., Mao, R., Pinedo, K., Roque, J., Richards, C., Stabile, M., Swaminathan, G., Salagianni, M., Triantafyllia, V., Bertrams, W., Blish, C., Carette, J., Frankovich, J., Meffre, E., Nadeau, K. C., Singh, U., Wang, T., Prak, E. L., Herold, S., Andreakos, E., Schmeck, B., Skevaki, C., Rogers, A., Utz, P. 2022

    Abstract

    The widespread presence of autoantibodies in acute infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is increasingly recognized, but the prevalence of autoantibodies in infections with organisms other than SARS-CoV-2 has not yet been reported. We used protein arrays to profile IgG autoantibodies from 317 samples from 268 patients across a spectrum of non-SARS-CoV-2 infections, many of whom were critically ill with pneumonia. Anti-cytokine antibodies (ACA) were identified in > 50% of patients infected with non-SARS-CoV-2 viruses and other pathogens, including patients with pneumonia attributed to bacterial causes. In cell-based functional assays, some ACA blocked binding to surface receptors for type I interferons (Type I IFN), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-6 (IL-6). Autoantibodies against traditional autoantigens associated with connective tissue diseases (CTDs) were also commonly observed in these cohorts, including newly-detected antibodies that emerged in longitudinal samples from patients infected with influenza. We conclude that autoantibodies, some of which are functionally active, may be much more prevalent than previously appreciated in patients who are symptomatically infected with diverse pathogens.

    View details for DOI 10.21203/rs.3.rs-1233038/v1

    View details for PubMedID 35075455

    View details for PubMedCentralID PMC8786233

  • IMMUNE MARKERS AND IMMUNOGENETICS IN PANS Frankovich, J. ELSEVIER SCIENCE INC. 2020: S286
  • Low C4 Copy Number of Total C4 Gene, C4B Gene and C4BL Gene in Children with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) Kalinowski, A., Lee, J., Hedlin, H., Pattini, R., Ollila, H., Mignot, E., Levinson, D., Swedo, S., Murphy, T., Chan, A., Thienemann, M., Urban, A., Frankovich, J. WILEY. 2020: 254–55
  • Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) Is Characterized by a Novel Subset of Monocytes with Markers Associated with Crossing the Blood Brain Barrier (BBB) Rahman, S., Gaertner, F., Houghton, J., Macaubas, C., Chan, A., Columbo, L., Frankovich, J., Mellins, E. WILEY. 2020: 262–63
  • Chronic Fatigue Symptoms in Children with Abrupt Early-onset OCD And/or PANS Chan, A., Truong, A., Farhadian, B., Willett, T., Silverman, M., Tran, P., Thienemann, M., Frankovich, J. WILEY. 2020: 252–54
  • Corrigendum to "Psychotic symptoms in youth with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) may reflect syndrome severity and heterogeneity" [J. Psychiatr. Res. 110 (2019) 93-102]. Journal of psychiatric research Silverman, M., Frankovich, J., Nguyen, E., Leibold, C., Yoon, J., Freeman, G. M., Karpel, H., Thienemann, M. 2019; 113: 45

    View details for PubMedID 30897370

  • Psychotic symptoms in youth with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) may reflect syndrome severity and heterogeneity JOURNAL OF PSYCHIATRIC RESEARCH Silverman, M., Frankovich, J., Nguyen, E., Leibold, C., Yoon, J., Freeman, G., Karpel, H., Thienemann, M. 2019; 110: 93–102
  • Action in the face of uncertainty? JOURNAL OF PEDIATRICS Thienemann, M., Frankovich, J. 2019; 204: 324
  • Psychometric Properties of the Pediatric Acute-Onset Neuropsychiatric Syndrome Global Impairment Score in Children and Adolescents with Pediatric Acute-Onset Neuropsychiatric Syndrome JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Leibold, C., Thienemann, M., Farhadian, B., Willett, T., Frankovich, J. 2019; 29 (1): 41–49
  • Action in the face of uncertainty? The Journal of pediatrics Thienemann, M., Frankovich, J. 2018

    View details for PubMedID 30318368

  • Response to editor regarding "Improvement of psychiatric symptoms in youth following resolution of sinusitis". International journal of pediatric otorhinolaryngology Frankovich, J., Sidell, D., Gans, H., Brown, K., Mahony, T., Thienemann, M. 2018; 112: 208–9

    View details for PubMedID 29050812

  • Allergic Diseases and Immune-Mediated Food Disorders in Pediatric Acute-Onset Neuropsychiatric Syndrome PEDIATRIC ALLERGY IMMUNOLOGY AND PULMONOLOGY Rosa, J. S., Hernandez, J. D., Sherr, J. A., Smith, B. M., Brown, K. D., Farhadian, B., Mahony, T., McGhee, S. A., Lewis, D. B., Thienemann, M., Frankovich, J. D. 2018; 31 (3): 158–65
  • Response to editor regarding "Improvement of psychiatric symptoms in youth following resolution of sinusitis" INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY Frankovich, J., Sidell, D., Gans, H., Brown, K., Mahony, T., Thienemann, M. 2018; 112: 208–9
  • Psychometric Evaluation of the Caregiver Burden Inventory in Children and Adolescents With PANS. Journal of pediatric psychology Farmer, C. n., Thienemann, M. n., Leibold, C. n., Kamalani, G. n., Sauls, B. n., Frankovich, J. n. 2018

    Abstract

    To establish the psychometric properties of the Caregiver Burden Inventory (CBI) in patients with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), which is characterized by the abrupt onset of obsessive-compulsive disorder and/or restricted eating and at least two additional psychiatric symptoms. Parents of patients with PANS have reported high caregiver burden. However, no validated instrument of burden exists for this population.Study took place at a community-based PANS clinic where the CBI is administered as part of routine clinical care. The first CBI available during an active disease flare was analyzed (N =104). Construct validity was evaluated within a confirmatory factor analytic framework. Associations between the CBI and patient/family characteristics were explored, and preliminary normative data for this population are presented.Item-factor loadings were strong, and the overall fit of the model was good (root mean square error of approximation = .061). Strict/metric measurement invariance was demonstrated across age. The mean Total Score in this sample was 36.72 ± 19.84 (interquartile range 19-53). Total Scores on the CBI were significantly elevated for parents of children who switched schools because of their illness (Cohen's d = 0.75, 95% confidence interval [CI] 0.28-1.22) and for those who had reduced work hours to accommodate the child's illness (Cohen's d = 0.65, 95% CI 0.10-1.20). However, in this relatively high-status sample, socioeconomic variables did not predict Total Scores.Parents of patients with PANS experience high caregiver burden. The CBI may be confidently used to assess caregiver burden in this population.

    View details for PubMedID 29547961

  • CLINICAL MANAGEMENT OF PEDIATRIC ACUTE-ONSET NEUROPSYCHIATRIC SYNDROME: USE OF IMMUNOMODULATORY THERAPIES Frankovich, J. ELSEVIER SCIENCE INC. 2017: S339
  • Comparing Presenting Clinical Features in 48 Children With Microscopic Polyangiitis to 183 Children Who Have Granulomatosis With Polyangiitis (Wegener's): An ARChiVe Cohort Study ARTHRITIS & RHEUMATOLOGY Cabral, D. A., Canter, D. L., Muscal, E., Nanda, K., Wahezi, D. M., Spalding, S. J., Twilt, M., Benseler, S. M., Campillo, S., Charuvanij, S., Dancey, P., Eberhard, B. A., Elder, M. E., Hersh, A., Higgins, G. C., Huber, A. M., Khubchandani, R., Kim, S., Klein-Gitelman, M., Kostik, M. M., Lawson, E. F., Lee, T., Lubieniecka, J. M., McCurdy, D., Moorthy, L. N., Morishita, K. A., Nielsen, S. M., O'Neil, K. M., Reiff, A., Ristic, G., Robinson, A. B., Sarmiento, A., Shenoi, S., Toth, M. B., Van Mater, H. A., Wagner-Weiner, L., Weiss, J. E., White, A. J., Yeung, R. S. 2016; 68 (10): 2514-2526

    Abstract

    To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA).The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons.In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n = 48) or GPA (n = 183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil.Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding.

    View details for DOI 10.1002/art.39729

    View details for PubMedID 27111558

  • INFLAMMATION AND PEDIATRIC OBSESSIVE-COMPULSIVE DISORDER-RELATED MENTAL ILLNESSES Frankovich, J. ELSEVIER SCIENCE INC. 2016: S267–S268
  • Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plans for New-Onset Polyarticular Juvenile Idiopathic Arthritis ARTHRITIS CARE & RESEARCH Ringold, S., Weiss, P. F., Colbert, R. A., DeWitt, E. M., Lee, T., Onel, K., Prahalad, S., Schneider, R., Shenoi, S., Vehe, R. K., Kimura, Y. 2014; 66 (7): 1063-1072

    Abstract

    There is no standardized approach to the initial treatment of polyarticular juvenile idiopathic arthritis (JIA) among pediatric rheumatologists. Understanding the comparative effectiveness of the diverse therapeutic options available will result in better health outcomes for polyarticular JIA. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans (CTPs) for use in clinical practice to facilitate such studies.A case-based survey was administered to CARRA members to identify the common treatment approaches for new-onset polyarticular JIA. Two face-to-face consensus conferences employed modified nominal group technique to identify treatment strategies, operational case definition, end points, and data elements to be collected. A core workgroup reviewed the relevant literature, refined plans, and developed medication dosing and monitoring recommendations.The initial case-based survey identified significant variability among treatment approaches for new-onset polyarticular JIA. We developed 3 CTPs based on treatment strategies for the first 12 months of therapy, as well as case definitions and clinical and laboratory monitoring schedules. The CTPs include a step-up plan (nonbiologic disease-modifying antirheumatic drug [DMARD] followed by a biologic DMARD), an early combination plan (nonbiologic and biologic DMARD combined within a month of treatment initiation), and a biologic only plan. This approach was approved by 96% of the CARRA JIA Research Committee members attending the 2013 CARRA face-to-face meeting.Three standardized CTPs were developed for new-onset polyarticular JIA. Coupled with data collection at defined intervals, use of these CTPs will enable the study of their comparative effectiveness in an observational setting to optimize initial management of polyarticular JIA.

    View details for DOI 10.1002/acr.22259

    View details for Web of Science ID 000337976700013

    View details for PubMedCentralID PMC4467832

  • Pilot Study of Reproductive Health Counseling in a Pediatric Rheumatology Clinic ARTHRITIS CARE & RESEARCH Ronis, T., Frankovich, J., Yen, S., Sandborg, C., Chira, P. 2014; 66 (4): 631-635

    Abstract

    Objective: To assess perception and behavior after reproductive health counseling among adolescent patients in a tertiary care-based pediatric rheumatology clinic. Methods: Adolescent females seen at Stanford pediatric rheumatology clinic were prospectively enrolled during routine visits. At study start, standard clinic procedures for the following were reviewed with providers: 1) HEADSS (home, education, activities, drugs, sexual activity, and suicide/depression) assessment; 2) reproductive health counseling; and 3) medical record documentation. Patients were enrolled if providers indicated that they performed HEADSS assessment and reproductive health counseling. At enrollment, patients completed a survey to assess perceptions of reproductive health counseling. Chart review confirmed documented discussions. Follow-up survey 3-5 months after enrollment tracked reproductive health information seeking behavior. Results: Ninety females (ages 17 ± 2 years old) participated. Almost all patients (99%) agreed that reproductive health was discussed. Seventy-one percent reported that pregnancy risks were discussed, 42% had recent concerns about reproductive health, and 33% reported their provider recommended that they seek further reproductive health care. Eighty-four patients completed follow-up phone surveys, with 25% reporting seeking further information on reproductive health concerns but merely 9.5% actually sought further care. Only 18% reported having ever asked their rheumatology provider for guidance regarding reproductive health care concerns. Conclusion: Routine reproductive health discussion and counseling are necessary in a rheumatology clinic; as in our experience, a substantial number of adolescents have concerns and actively seek reproductive health information. Despite these discussions, teens rarely pursued further reproductive health care. Further work to bridge this gap is needed.

    View details for DOI 10.1002/acr.22159

    View details for Web of Science ID 000333380400017

    View details for PubMedCentralID PMC4087090

  • Pilot study of reproductive health counseling in a pediatric rheumatology clinic. Arthritis care & research Ronis, T., Frankovich, J., Yen, S., Sandborg, C., Chira, P. 2014; 66 (4): 631-635

    Abstract

    Objective: To assess perception and behavior after reproductive health counseling among adolescent patients in a tertiary care-based pediatric rheumatology clinic. Methods: Adolescent females seen at Stanford pediatric rheumatology clinic were prospectively enrolled during routine visits. At study start, standard clinic procedures for the following were reviewed with providers: 1) HEADSS (home, education, activities, drugs, sexual activity, and suicide/depression) assessment; 2) reproductive health counseling; and 3) medical record documentation. Patients were enrolled if providers indicated that they performed HEADSS assessment and reproductive health counseling. At enrollment, patients completed a survey to assess perceptions of reproductive health counseling. Chart review confirmed documented discussions. Follow-up survey 3-5 months after enrollment tracked reproductive health information seeking behavior. Results: Ninety females (ages 17 ± 2 years old) participated. Almost all patients (99%) agreed that reproductive health was discussed. Seventy-one percent reported that pregnancy risks were discussed, 42% had recent concerns about reproductive health, and 33% reported their provider recommended that they seek further reproductive health care. Eighty-four patients completed follow-up phone surveys, with 25% reporting seeking further information on reproductive health concerns but merely 9.5% actually sought further care. Only 18% reported having ever asked their rheumatology provider for guidance regarding reproductive health care concerns. Conclusion: Routine reproductive health discussion and counseling are necessary in a rheumatology clinic; as in our experience, a substantial number of adolescents have concerns and actively seek reproductive health information. Despite these discussions, teens rarely pursued further reproductive health care. Further work to bridge this gap is needed.

    View details for PubMedID 24022992

  • Teens' Perception of Reproductive Health Counseling in Pediatric Rheumatology. Ronis, T., Frankovich, J. D., Sandborg, C. I., Chira, P. WILEY-BLACKWELL. 2011: S800–S801
  • Laboratory markers of cardiovascular risk in pediatric SLE: the APPLE baseline cohort LUPUS Ardoin, S. P., Schanberg, L. E., Sandborg, C., Yow, E., Barnhart, H. X., Mieszkalski, K. L., Ilowite, N. T., von Scheven, E., Eberhard, A., Levy, D. M., Kimura, Y., Silverman, E., Bowyer, S. L., Punaro, L., Singer, N. G., Sherry, D. D., McCurdy, D., Klein-Gitelman, M., Wallace, C., Silver, R., Wagner-Weiner, L., Higgins, G. C., Brunner, H. I., Jung, L. K., Imundo, L., Soep, J. B., Reed, A. M. 2010; 19 (11): 1315-1325

    Abstract

    As part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Trial, a prospective multicenter cohort of 221 children and adolescents with systemic lupus erythematosus (SLE) (mean age 15.7 years, 83% female) underwent baseline measurement of markers of cardiovascular risk, including fasting levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), lipoprotein A (Lpa), homocysteine and high-sensitivity C-reactive protein (hs-CRP). A cross-sectional analysis of the baseline laboratory values and clinical characteristics of this cohort was performed. Univariable relationships between the cardiovascular markers of interest and clinical variables were assessed, followed by multivariable linear regression modeling. Mean levels of LDL, HDL, Lpa, TG, hs-CRP and homocysteine were in the normal or borderline ranges. In multivariable analysis, increased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), prednisone dose, and hypertension (HTN) were independently associated with higher LDL levels. Higher hs-CRP and creatinine clearance were independently related to lower HDL levels. Higher body mass index (BMI), prednisone dose, and homocysteine levels were independently associated with higher TG levels. Only Hispanic or non-White status predicted higher Lpa levels. Proteinuria, higher TG and lower creatinine clearance were independently associated with higher homocysteine levels, while use of multivitamin with folate predicted lower homocysteine levels. Higher BMI, lower HDL, and longer SLE disease duration, but not SLEDAI, were independently associated with higher hs-CRP levels. The R(2) for these models ranged from 7% to 23%. SLE disease activity as measured by the SLEDAI was associated only with higher LDL levels and not with hs-CRP. Markers of renal injury (HTN, proteinuria, and creatinine clearance) were independently associated with levels of LDL, HDL, and homocysteine, highlighting the importance of renal status in the cardiovascular health of children and adolescents with SLE. Future longitudinal analysis of the APPLE cohort is needed to further examine these relationships.

    View details for DOI 10.1177/0961203310373937

    View details for Web of Science ID 000282090700007

    View details for PubMedID 20861207

  • A TGF beta-Responsive Gene Signature Is Associated with a Subset of Diffuse Scleroderma with Increased Disease Severity JOURNAL OF INVESTIGATIVE DERMATOLOGY Sargent, J. L., Milano, A., Bhattacharyya, S., Varga, J., Connolly, M. K., Chang, H. Y., Whitfield, M. L. 2010; 130 (3): 694-705

    Abstract

    Systemic sclerosis is a complex disease with widespread skin fibrosis and variable visceral organ involvement. Since transforming growth factor-beta (TGFbeta) has been implicated in driving fibrosis in systemic sclerosis, a mechanism-derived gene expression signature was used to assay TGFbeta-responsive gene expression in the skin of patients with systemic sclerosis (SSc). Primary dermal fibroblasts from patients with diffuse SSc (dSSc) and healthy controls were treated with TGFbeta, and the genome-wide gene expression was measured on DNA microarrays over a time course of 24 hours. Eight hundred and ninety-four probes representing 674 uniquely annotated genes were identified as TGFbeta responsive. Expression of the TGFbeta-responsive signature was examined in skin biopsies from 17 dSSc, seven limited SSc (lSSc), three morphea patients, and six healthy controls. The TGFbeta-responsive signature was expressed in 10 out of 17 dSSc skin biopsies, but was not found in lSSc, morphea, or healthy control biopsies. Expression of dSSC the TGFbeta-responsive signature stratifies patients into two major groups, one of which corresponds to the "diffuse-proliferation" intrinsic subset that showed higher modified Rodnan skin score and a higher likelihood of scleroderma lung disease. The TGFbeta-responsive signature is found in only a subset of dSSc patients who could be targeted by specific therapies.

    View details for DOI 10.1038/jid.2009.318

    View details for Web of Science ID 000275017600013

    View details for PubMedID 19812599

  • Classification, Presentation, and Initial Treatment of Wegener's Granulomatosis in Childhood ARTHRITIS AND RHEUMATISM Cabral, D. A., Uribe, A. G., Benseler, S., O'Neil, K. M., Hashkes, P. J., Higgins, G., Zeft, A. S., Lovell, D. J., Kingsbury, D. J., Stevens, A., McCurdy, D., Chira, P., Abramson, L., Arkachaisri, T., Campillo, S., Eberhard, A., Hersh, A. O., Huber, A. M., Kim, S., Klein-Gitelman, M., Levy, D. M., Li, S. C., Mason, T., DeWitt, E. M., Muscal, E., Nassi, L., Reiff, A., Schikler, K., Singer, N. G., Wahezi, D., Woodward, A. 2009; 60 (11): 3413-3424

    Abstract

    To compare the criteria for Wegener's granulomatosis (WG) of the American College of Rheumatology (ACR) with those of the European League Against Rheumatism/Pediatric Rheumatology European Society (EULAR/PRES) in a cohort of children with WG and other antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs), and to describe the interval to diagnosis, presenting features, and initial treatment for WG.Eligible patients had been diagnosed by site rheumatologists (termed the "MD diagnosis") since 2004. This diagnosis was used as a reference standard for sensitivity and specificity testing of the 2 WG classification criteria. Descriptive analyses were confined to ACR-classified WG patients.MD diagnoses of 117 patients (82 of whom were female) were WG (n = 76), microscopic polyangiitis (n = 17), ANCA-positive pauci-immune glomerulonephritis (n = 5), Churg-Strauss syndrome (n = 2), and unclassified vasculitis (n = 17). The sensitivities of the ACR and EULAR/PRES classification criteria for WG among the spectrum of AAVs were 68.4% and 73.6%, respectively, and the specificities were 68.3% and 73.2%, respectively. Two more children were identified as having WG by the EULAR/PRES criteria than by the ACR criteria. For the 65 ACR-classified WG patients, the median age at diagnosis was 14.2 years (range 4-17 years), and the median interval from symptom onset to diagnosis was 2.7 months (range 0-49 months). The most frequent presenting features by organ system were constitutional (89.2%), pulmonary (80.0%), ear, nose, and throat (80.0%), and renal (75.4%). Fifty-four patients (83.1%) commenced treatment with the combination of corticosteroids and cyclophosphamide, with widely varying regimens; the remainder received methotrexate alone (n = 1), corticosteroids alone (n = 4), or a combination (n = 6).The EULAR/PRES criteria minimally improved diagnostic sensitivity and specificity for WG among a narrow spectrum of children with AAVs. Diagnostic delays may result from poor characterization of childhood WG. Initial therapy varied considerably among participating centers.

    View details for DOI 10.1002/art.24876

    View details for Web of Science ID 000271781400031

    View details for PubMedID 19877069

  • High-dose therapy and autologous hematopoietic cell transplantation in children with primary refractory and relapsed Hodgkin's disease: Atopy predicts idiopathic diffuse lung injury syndromes BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Frankovich, J., Donaldson, S. S., Lee, Y. B., Wong, R. M., Amylon, M., Verneris, M. R. 2001; 7 (1): 49-57

    Abstract

    The use of high-dose therapy (HDT) and autologous hematopoietic cell transplantation (AHCT) for children and adolescents with primary refractory and relapsed Hodgkin's disease is increasing. The purpose of this retrospective analysis was to: (1) evaluate the outcome of HDT and AHCT in pediatric patients with Hodgkin's disease, and (2) identify factors that predispose patients to the development of transplantation-related complications. We describe the experiences of 34 pediatric patients from a single institution with primary refractory or relapsed Hodgkin's disease. HDT regimens consisted of cyclophosphamide and etoposide combined with either carmustine, chloroethylcyclohexylnitrosurea, or fractionated total body irradiation. Kaplan-Meier survival predicts that 67% (95% confidence interval [CI] 47%-87%) of patients will be alive and disease-free at 5 years. Nine patients had disease recurrence, of whom 5 relapsed after 1 year (1.5-6.3 years). Five patients succumbed to treatment-related toxicities, of whom 4 died of pulmonary failure. Fifteen patients (44%) developed post-AHCT idiopathic diffuse lung injury syndrome: acute alveolitis (n = 2); diffuse alveolar hemorrhage (n = 2); acute respiratory distress syndrome (n = 2); delayed interstitial pneumonitis (n = 8); and bronchiolitis obliterans (n = 1). The following factors did not predict for the development of a diffuse lung injury syndrome in univariate analysis: prior treatment with bleomycin, pre-HDT pulmonary function tests, and prior thoracic irradiation. Of the patients in our cohort, 44% had a history of atopy (allergic rhinitis and/or asthma). Multivariate logistic analysis revealed that a preexisting history of atopy was highly predictive of idiopathic pulmonary complications (P = .0001, odds ratio = 21, CI 3.6-125). Our experience shows that HDT followed by AHCT results in durable remissions in two thirds of pediatric patients with refractory and relapsed Hodgkin's disease, and a history of atopy is associated with post-AHCT pulmonary complications.

    View details for PubMedID 11215699

  • DISSOCIATION OF MINOR SATELLITE FROM THE CENTROMERE IN MOUSE JOURNAL OF CELL SCIENCE Vig, B. K., Latour, D., Frankovich, J. 1994; 107: 3091-3095

    Abstract

    The minor satellite DNA of mouse is believed to constitute the centromere. We report that centromeres of some chromosomes in the Cl1D cells of mouse are not associated with this DNA even though the latter is present on these chromosomes. The satellite DNA was detected distally from the centromere and could not be mistaken as a component of the centromere. We also report that the site of the primary constriction may not always coincide with the site of the anti-kinetochore antibody reaction. Whereas the regions containing the major satellite decondense upon treatment with bisbenzimidazole (Hoechst 33258), the sites carrying minor satellite resist decondensing.

    View details for Web of Science ID A1994PV95900012

    View details for PubMedID 7535306

  • COMPARISON OF THE ACTIONS OF ACETYLCHOLINE AND BRL-38227 IN THE GUINEA-PIG CORONARY-ARTERY BRITISH JOURNAL OF PHARMACOLOGY Eckman, D. M., FRANKOVICH, J. D., Keef, K. D. 1992; 106 (1): 9-16

    Abstract

    1. The contractile and electrical responses to acetylcholine (ACh) in isolated segments of guinea-pig and rabbit coronary arteries were compared to those of the putative adenosine 5'-triphosphate (ATP)-dependent K+ channel opener, BRL 38227. 2. Both ACh and BRL 38227 produced concentration-dependent relaxation of vessel segments contracted with the H1-receptor agonist, 2-(2-aminoethyl)pyridine. 3. An IC90 of either vasodilator also produced 17-20 mV of hyperpolarization of the guinea-pig coronary artery. 4. Glibenclamide (1-35 microM) depolarized the guinea-pig coronary artery by 8-12 mV and antagonized BRL 38227- but not ACh-induced relaxation and hyperpolarization. 5. In the guinea-pig coronary artery, the K+ channel blockers phencyclidine (PCP, 100 microM), tetraethylammonium (TEA, 10 mM) and scorpion venom (8.7 micrograms ml-1) all significantly reduced ACh-induced relaxation and hyperpolarization whereas only PCP was an effective antagonist of both relaxation and hyperpolarization with BRL 38227. 6. Similar effects of glibenclamide and scorpion venom on ACh- and BRL 38227-induced relaxation were observed in the rabbit coronary artery. 7. Apamin (3.5 microM) was without effect on either the ACh- or BRL 38227-induced relaxation in the guinea-pig coronary artery. 8. In conclusion, the actions of BRL 38227 in coronary artery are compatible with its proposed effects on ATP-dependent K+ channels. In contrast, the results with ACh suggest that some step between the initial binding of ACh to endothelial muscarinic receptors and the final relaxation of the smooth muscle depends upon the opening of Ca(2+)-activated K+ channels.

    View details for Web of Science ID A1992HT20900002

    View details for PubMedID 1504734